0%
HTRA1c.1333G>AUncertain significance
Print report
Variant interpretation report

HTRA1 c.1333G>A, p.(Ala445Thr)

NM_002775.4:c.1333G>A NP_002766.1:p.(Ala445Thr) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About HTRA1

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting

The variant p.Ala445Thr is located within the peptidase S1 (trypsin-like serine protease) domain (residues 157–473), a well-established critical functional domain. Loss of HTRA1 protease activity through missense variants in this domain is the established mechanism for cerebral small vessel disease (CARASIL/CADASIL2). Published literature confirms that missense variants clustering in the protease domain are a common cause of monogenic CSVD.

PM2Supporting
PM2 · supporting

This variant is present at very low frequency in population databases. gnomAD v2.1 reports an allele frequency of 0.01237% (35/282,868 alleles, 0 homozygotes) and gnomAD v4.1 reports 0.01041% (168/1,613,814 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0. The highest subpopulation frequency is 0.028% (Admixed American, v2.1) and 0.083% (Middle Eastern, v4.1), both below 0.1%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.133 (well below pathogenic threshold of 0.5). BayesDel score is -0.219368 (negative, consistent with a benign prediction). SpliceAI predicts no splice alteration (max delta = 0.00). These three independent in silico predictors converge on a neutral/benign interpretation.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
168 / 1,613,814 alleles

gnomAD v4.1: 168 / 1,613,814 alleles. Recorded AF 0.000104101. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000123733; MAF= 0.01237%, 35/282868 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000282167; MAF= 0.02822%, 10/35440 alleles, homozygotes = 0); grpmax FAF= 0.00015644.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions

7 Uncertain significance.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64564366, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 19 not met · 2 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002775.4:c.1333G>A (p.Ala445Thr) is a missense variant in HTRA1 located within the peptidase S1 serine protease domain (residues 157–473), a well-established functional domain critical for HTRA1 protease activity. Loss-of-function missense variants in this domain are a known cause of cerebral small vessel disease including CARASIL and CADASIL2.

This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency is 0.012% (35/282,868 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency is 0.010% (168/1,613,814 alleles, 0 homozygotes). The variant is absent from gnomAD-Canada. All frequencies fall well below the 0.1% PM2 threshold.

Multiple in silico predictors suggest a neutral effect: REVEL score is 0.133 (below pathogenic threshold), BayesDel score is −0.219 (negative, favoring benign), and SpliceAI predicts no splice alteration (max delta = 0.00). These orthogonal computational lines of evidence support a benign interpretation.

This variant has been reported in ClinVar (Variation ID 877269) as Uncertain significance by 8 clinical submitters with no expert panel review. No pathogenic or benign assertions have been made by a reputable source. All 16 associated PMIDs are policy or guideline documents unrelated to this specific variant.

No functional studies (PS3/BS3), case-control data (PS4), de novo observations (PS2/PM6), segregation data (PP1/BS4), or same-residue pathogenic comparators (PS5/PM5) were identified for this variant in the published literature or databases.

Applying generic ACMG/AMP 2015 combination rules: PM1_Supporting + PM2_Supporting versus BP4_Supporting results in two opposing supporting-level criteria. Since no criterion reaches moderate or higher strength on either side, and the evidence is balanced with low-confidence signals in both directions, the final classification defaults to Variant of Uncertain Significance (VUS).

Met · 3

PM1 SupportingThe variant p.Ala445Thr is located within the peptidase S1 (trypsin-like serine protease) domain (residues 157–473), a well-established critical functional domain. Loss of HTRA1 protease activity through missense variants in this domain is the established mechanism for cerebral small vessel disease (CARASIL/CADASIL2). Published literature confirms that missense variants clustering in the protease domain are a common cause of monogenic CSVD. Details ▾Hide ▴
Evidence considered
  • UniProt (P83110) annotates the peptidase S1 domain spanning residues 157–473
  • p.Ala445Thr falls within this domain.
  • PMID:28126975: HTRA1 loss of protease activity via mutations in the protease domain causes CARASIL.
  • PMID:40607620: Heterozygous HTRA1 missense variants cause autosomal dominant CSVD (CADASIL2)
  • all 15 variants were functionally validated in the protease domain.
  • Hotspots analysis confirms residue-level significance is not established
  • but domain-level pathogenicity is well documented.
Still missing
  • No formal hot-spot statistical analysis for residue Ala445 specifically
  • PM1 applied at supporting level based on domain-level evidence.
Sources
pvs1_gene_context2812697540607620
PM2 SupportingThis variant is present at very low frequency in population databases. gnomAD v2.1 reports an allele frequency of 0.01237% (35/282,868 alleles, 0 homozygotes) and gnomAD v4.1 reports 0.01041% (168/1,613,814 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0. The highest subpopulation frequency is 0.028% (Admixed American, v2.1) and 0.083% (Middle Eastern, v4.1), both below 0.1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.01237% (35/282
  • 868)
  • 0 homozygotes
  • grpmax FAF=0.0156%.
  • gnomAD v4.1: AF=0.01041% (168/1
  • 613
  • 814)
  • grpmax FAF=0.0326%.
  • gnomAD-Canada v1.0: absent (0 alleles).
  • All subpopulation AFs and grpmax FAF values are below 0.1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.133 (well below pathogenic threshold of 0.5). BayesDel score is -0.219368 (negative, consistent with a benign prediction). SpliceAI predicts no splice alteration (max delta = 0.00). These three independent in silico predictors converge on a neutral/benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.133 (threshold for pathogenic typically ≥0.5
  • this score is low).
  • BayesDel: -0.219368 (negative score supports a benign interpretation).
  • SpliceAI max delta: 0.00 (no predicted splicing impact).
  • All three orthogonal predictors agree on a neutral prediction.
Sources
revelbayesdelspliceai ↗

Not met · 19 · evaluated, threshold not reached

PS2 No confirmed de novo occurrence of NM_002775.4:c.1333G>A with established maternity and paternity was identified in the literature or databases. PS2 requires a proven de novo event in a patient with the disease and no family history. Details ▾Hide ▴
Evidence considered
  • Targeted literature search (PubMed
  • ClinVar) yielded no de novo reports for this variant.
  • Exploratory evidence recovery confirmed no de novo observations with confirmed parentage.
Still missing
  • No de novo case reports or family studies documenting this variant with confirmed parentage.
PS3 No well-established in vitro or in vivo functional studies specifically assessing the damaging effect of p.Ala445Thr on HTRA1 protease activity were identified. The ClinVar-associated PMIDs (25741868, 26467025) are methodological guidelines, not variant-specific functional studies. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence recovery searched PubMed for HTRA1 Ala445Thr functional studies
  • none found.
  • ClinVar-submitted PMIDs (25741868
  • 26467025) are ACMG/AMP and Sherloc methodological papers
  • not variant-specific functional evidence.
Still missing
  • No published functional characterization of the p.Ala445Thr substitution (e.g.
  • protease activity assay
  • TGF-beta signaling readout).
Sources
2574186826467025
PS4 No case-control study or statistical enrichment analysis has been performed for this variant in HTRA1-associated disease. ClinVar lists the variant as Uncertain significance from clinical laboratories, but without validated cohort data or quantified prevalence in affected individuals, PS4 cannot be applied. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 877269: 8 submissions
  • all classified as Uncertain significance.
  • No case-control data or odds-ratio calculation comparing variant frequency in affected vs. controls.
Still missing
  • Absence of formal case-control study or statistically significant enrichment in HTRA1-affected cohorts.
Sources
clinvar ↗
PM5 PM5 requires a different pathogenic missense change at the same amino acid residue. The systematic PM5 candidate search identified no same-residue pathogenic comparators for residue Ala445 in HTRA1. Details ▾Hide ▴
Evidence considered
  • PM5 candidate collection returned 0 candidates at residue Ala445.
  • No known pathogenic variant at this residue is recorded in ClinVar or reported in the literature.
Still missing
  • No pathogenic missense variant at HTRA1 residue Ala445 identified.
Sources
pm5_candidates
PM6 No assumed de novo occurrence (without confirmation of parentage) has been reported for this variant. Exploratory evidence recovery found no such observations. Details ▾Hide ▴
Evidence considered
  • Exploratory recovery searched for de novo HTRA1 variants
  • no reports for c.1333G>A.
Still missing
  • No de novo observation
  • even unconfirmed
  • identified in the literature.
PP1 No co-segregation data for this variant in multiple affected family members were identified. PP1 requires the variant to co-segregate with disease in a family; no such published pedigree includes c.1333G>A. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence recovery found no familial segregation studies for c.1333G>A.
Still missing
  • No published pedigree with c.1333G>A showing co-segregation with HTRA1-associated CSVD.
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense is a common disease mechanism. While HTRA1 missense variants are a known mechanism for CSVD, no formal constraint metric (e.g., missense Z-score, gnomAD constraint) was evaluated to demonstrate a low rate of benign missense variation for this gene. The evidence is insufficient to apply PP2. Details ▾Hide ▴
Evidence considered
  • HTRA1 is associated with CARASIL and CADASIL2 through both recessive and dominant missense variants.
  • No missense constraint data (Z-score
  • LOEUF
  • or missense o/e) was identified in the evidence packet.
Still missing
  • No formal constraint metric for benign missense variation rate in HTRA1 was evaluated.
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.133 (well below the pathogenic threshold of 0.5). BayesDel score is -0.219368 (negative, indicating a benign prediction). SpliceAI predicts no splice impact (max delta score = 0.00). No in silico evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.133 (range 0–1
  • higher = more pathogenic
  • typical threshold ≥0.5).
  • BayesDel score: -0.219368 (negative
  • range typically -1 to +1
  • negative scores favor benign).
  • SpliceAI max delta: 0.00 (no predicted splice alteration).
  • HCI Prior: not available for HTRA1.
Sources
revelbayesdelspliceai ↗
PP4 No detailed patient phenotype or family history data specific to this variant were available. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease. Insufficient clinical information was available. Details ▾Hide ▴
Still missing
  • No specific patient phenotype
  • family history
  • or clinical data linked to c.1333G>A were provided.
PP5 No reputable source has classified this variant as pathogenic. ClinVar records 8 submissions, all reporting Uncertain significance. No expert panel or clinical laboratory has asserted a pathogenic or likely pathogenic classification. All associated PMIDs are policy/guideline documents that do not discuss this specific variant. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 877269: 8 submissions
  • all Uncertain significance
  • 0 expert panel submissions.
  • All 16 associated PMIDs are newborn screening
  • carrier screening
  • or genetic testing policy papers — none mention c.1333G>A.
Still missing
  • No reputable source has classified c.1333G>A as pathogenic.
Sources
clinvar ↗20437615229472992303793323169492236192752365237823881473240222982412114724394680256267072573023025741868264670252849253231022120
BA1 BA1 requires an allele frequency >1% in any population database. gnomAD v2.1 total AF is 0.01237% and v4.1 total AF is 0.01041%. The highest subpopulation frequency is 0.083% (Middle Eastern, v4.1). All observed frequencies are well below 1%. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: max subpopulation AF=0.028% (Admixed American).
  • gnomAD v4.1: max subpopulation AF=0.083% (Middle Eastern).
  • All frequencies are orders of magnitude below the 1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 BS1 requires an allele frequency >0.3% in population databases. gnomAD v2.1 total AF is 0.01237% and v4.1 total AF is 0.01041%. The grpmax FAF is 0.0156% (v2.1) and 0.0326% (v4.1), both well below 0.3%. The highest subpopulation frequency is 0.083% (Middle Eastern, v4.1). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.01237%
  • grpmax FAF=0.0156%.
  • gnomAD v4.1: AF=0.01041%
  • grpmax FAF=0.0326%.
  • All frequencies are below the 0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of this variant in a healthy adult individual has been reported for a disorder assumed to be fully penetrant. BS2 requires documented presence in a healthy adult for a dominant disorder, which has not been established for c.1333G>A. Details ▾Hide ▴
Still missing
  • No documented observation of c.1333G>A in a healthy adult with full clinical evaluation.
BS3 No well-established functional studies demonstrating a neutral effect of p.Ala445Thr on HTRA1 protease activity were identified. The ClinVar-associated PMIDs assigned to BS3 (25741868, 26467025) are ACMG/AMP and Sherloc methodological guidelines, not variant-specific functional studies. Details ▾Hide ▴
Evidence considered
  • No published functional assay demonstrating that p.Ala445Thr retains normal HTRA1 protease activity.
  • PMID:25741868 and PMID:26467025 are classification framework papers
  • not variant-specific functional studies.
Still missing
  • No experimental evidence demonstrating neutral functional effect of p.Ala445Thr.
Sources
2574186826467025
BS4 No evidence of non-segregation with disease in affected members of a family was identified. BS4 requires the variant to be absent in an affected family member or present in unaffected family members, thereby reducing pathogenicity likelihood. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence recovery found no family segregation studies for c.1333G>A.
Still missing
  • No published family data showing non-segregation of c.1333G>A with HTRA1-associated disease.
BP1 BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. HTRA1-associated cerebral small vessel disease is caused by both missense and truncating variants; published cohorts (PMID:40607620, PMID:28126975) demonstrate that missense variants in the protease domain are a common pathogenic mechanism. Therefore, BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • PMID:28126975: Both missense and truncating HTRA1 variants cause CARASIL.
  • PMID:40607620: Heterozygous missense HTRA1 variants are a well-established cause of autosomal dominant CSVD (CADASIL2).
  • HTRA1 is not a gene where primarily truncating variants cause disease
  • missense variants are a predominant mechanism.
Sources
2812697540607620
BP2 No observation of this variant in trans with a dominant pathogenic variant or in cis with a recessive pathogenic HTRA1 variant was identified. Exploratory evidence recovery found no such phased observations. Details ▾Hide ▴
Evidence considered
  • No ClinVar or literature reports of c.1333G>A in a phase relationship satisfying BP2.
Still missing
  • No phasing data for c.1333G>A with other HTRA1 variants identified.
BP5 No case was identified in which this variant co-occurs with an alternate molecular basis for the observed disease phenotype. BP5 requires observation in a patient with an alternative definitive genetic cause. Details ▾Hide ▴
Still missing
  • No report of c.1333G>A co-occurring with a definitive alternate molecular diagnosis.
BP6 No reputable source has classified this variant as benign. BP6 requires classification as benign or likely benign by a reputable source (e.g., clinical laboratory with established methodology). All ClinVar submissions for Variation ID 877269 classify this variant as Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 877269: All 8 submissions are Uncertain significance
  • 0 benign or likely benign assertions.
  • No expert panel or reputable clinical laboratory has classified this variant as benign.
Still missing
  • No reputable source has classified c.1333G>A as benign.
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

PS1 PS1 requires the same amino acid change (p.Ala445Thr) to have been reported as pathogenic via a different nucleotide change (e.g., c.1333G>C). No such variant was identified in ClinVar or the literature. This criterion cannot be assessed without a validated same-residue comparator. Details ▾Hide ▴
Still missing
  • No alternative nucleotide change producing p.Ala445Thr (e.g.
  • c.1333G>C) was identified in ClinVar or publications.
PS5 PS5 requires a different pathogenic missense change at the same amino acid residue (p.Ala445). No such pathogenic variant at residue 445 was identified in ClinVar, COSMIC, or the literature. PM5 candidate search also returned no comparators. Details ▾Hide ▴
Still missing
  • No known pathogenic variant at residue Ala445 of HTRA1 was identified for comparison.
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_002775.4:c.1333G>A is a missense substitution (p.Ala445Thr) and does not fall into any PVS1 null-variant bucket. The generic PVS1 framework (PMC6185798) confirms ineligibility. Details ▾Hide ▴
Evidence considered
  • This variant is a missense change (c.1333G>A
  • p.Ala445Thr) in exon 9 of HTRA1.
  • VariantValidator and Mutalyzer confirm a substitution at coding position 1333.
  • ClinGen SVI PVS1 recommendations (PMC6185798) restrict PVS1 to null variants
  • missense variants are excluded.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 applies exclusively to synonymous (silent) variants. NM_002775.4:c.1333G>A is a missense variant resulting in p.Ala445Thr and is not eligible for BP7 assessment. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
HTRA1
Transcript
NM_002775.4
Coding (HGVS c.)
NM_002775.4:c.1333G>A
Protein (HGVS p.)
NP_002766.1:p.(Ala445Thr)
GRCh38
chr10:122514249 G>A
GRCh37
chr10:124273765 G>A
ClinVar
877269
COSMIC
COSV64564366

Gene diagram

Every interpreted variant in HTRA1, mapped onto the exon structure of NM_002775.4. Select a row to find it on the plot.

HTRA1NM_002775.4
Fetching transcript structure from UCSC…
gnomAD v4.1 168 / 1,613,814 alleles AF 0.000104 · 0 homozygotes · FAF 0.000326
gnomAD v2.1 35 / 282,868 alleles AF 0.000124 · 0 homozygotes · FAF 0.000156
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 0.0001 · 168 / 1,613,814 alleles · 0 hom · FAF 0.00033
Middle Eastern5 / 6,030 0.00083
Remaining individuals21 / 62,492 0.00034
African/African American20 / 75,008 0.00027
Admixed American13 / 60,014 0.00022
European (non-Finnish)105 / 1,179,802 8.9e-05
South Asian3 / 91,064 3.3e-05
East Asian1 / 44,866 2.2e-05
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00012 · 35 / 282,868 alleles · 0 hom · FAF 0.00016
Admixed American10 / 35,440 0.00028
Remaining individuals2 / 7,224 0.00028
African/African American5 / 24,958 0.0002
European (non-Finnish)17 / 129,188 0.00013
South Asian1 / 30,616 3.3e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000104101; MAF= 0.01041%, 168/1613814 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000829187; MAF= 0.08292%, 5/6030 alleles, homozygotes = 0); grpmax FAF= 0.00032642.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000123733; MAF= 0.01237%, 35/282868 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000282167; MAF= 0.02822%, 10/35440 alleles, homozygotes = 0); grpmax FAF= 0.00015644.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -58 bp
0.000
SpliceAI acceptor gainat -147 bp
0.000
SpliceAI donor lossat +60 bp
0.000
SpliceAI donor gainat +332 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.133
BayesDel
-0.219

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.133 (well below pathogenic threshold of 0.5). BayesDel score is -0.219368 (negative, consistent with a benign prediction). SpliceAI predicts no splice alteration (max delta = 0.00). These three independent in silico predictors converge on a neutral/benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.133 (threshold for pathogenic typically ≥0.5
  • this score is low).
  • BayesDel: -0.219368 (negative score supports a benign interpretation).
  • SpliceAI max delta: 0.00 (no predicted splicing impact).
  • All three orthogonal predictors agree on a neutral prediction.
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.133 (well below the pathogenic threshold of 0.5). BayesDel score is -0.219368 (negative, indicating a benign prediction). SpliceAI predicts no splice impact (max delta score = 0.00). No in silico evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.133 (range 0–1
  • higher = more pathogenic
  • typical threshold ≥0.5).
  • BayesDel score: -0.219368 (negative
  • range typically -1 to +1
  • negative scores favor benign).
  • SpliceAI max delta: 0.00 (no predicted splice alteration).
  • HCI Prior: not available for HTRA1.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies exclusively to synonymous (silent) variants. NM_002775.4:c.1333G>A is a missense variant resulting in p.Ala445Thr and is not eligible for BP7 assessment. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.133. BayesDel score = -0.219368.

14 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • ACMG position statement on prenatal/preconception expanded carrier screening.
    No paper-specific finding is recorded.
    PMID 23619275 ↗
  • A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.
    Cornel MC et al. · 2014
    No paper-specific finding is recorded.
    PMID 23652378 ↗
  • Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.
    Howard HC et al. · 2015
    No paper-specific finding is recorded.
    PMID 25626707 ↗
  • Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.
    Edwards JG et al. · 2015
    No paper-specific finding is recorded.
    PMID 25730230 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • PMID:20437615
    No paper-specific finding is recorded.
    PMID 20437615 ↗
  • The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.
    Fears R et al. · 2013
    No paper-specific finding is recorded.
    PMID 23169492 ↗
  • Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.
    Langer A et al. · 2012
    No paper-specific finding is recorded.
    PMID 22947299 ↗
  • Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.
    Therrell BL et al. · 2013
    No paper-specific finding is recorded.
    PMID 23037933 ↗
  • Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.
    Blout C et al. · 2014
    No paper-specific finding is recorded.
    PMID 23881473 ↗
  • Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].
    Skirton H et al. · 2014
    No paper-specific finding is recorded.
    PMID 24022298 ↗
  • Parental permission for pilot newborn screening research: guidelines from the NBSTRN.
    Botkin JR et al. · 2014
    No paper-specific finding is recorded.
    PMID 24394680 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 168 / 1,613,814 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 7 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000104101; MAF= 0.01041%, 168/1613814 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000829187; MAF= 0.08292%, 5/6030 alleles, homozygotes = 0); grpmax FAF= 0.00032642.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000123733; MAF= 0.01237%, 35/282868 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000282167; MAF= 0.02822%, 10/35440 alleles, homozygotes = 0); grpmax FAF= 0.00015644.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 877269)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.133. BayesDel score = -0.219368.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64564366, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.