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HTRA1c.333G>AUncertain significance
Print report
Variant interpretation report

HTRA1 c.333G>A, p.(Val111=)

NM_002775.4:c.333G>A NP_002766.1:p.(Val111=) 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: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

PM2 (absent or extremely low frequency in population databases) is met at supporting strength. NM_002775.4:c.333G>A is absent from gnomAD v2.1 and is present in gnomAD v4.1 at an allele frequency of 6.56e-7 (1/1,524,404 alleles), well below the generic ACMG PM2 threshold of 0.1%. It is also absent from gnomAD-Canada v1.0.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

BP4 (multiple lines of computational evidence suggest no impact on gene product) is met at supporting benign strength. REVEL score is 0.041, strongly favoring a benign interpretation (typical pathogenic threshold >0.5). SpliceAI max delta score is 0.00, predicting no splicing alteration. Together these indicate no computational evidence of a deleterious effect.

BP7Supporting
BP7 · supporting

BP7 (synonymous variant with no predicted splicing impact and nucleotide not highly conserved) is met at supporting benign strength. NM_002775.4:c.333G>A is a synonymous variant (p.Val111=). SpliceAI predicts no splicing alteration (max delta = 0.00). The low REVEL score (0.041) indicates the nucleotide position is not highly conserved across species.

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: PM2 supporting, BP4 supporting benign, BP7 supporting benign; combination = 1 supporting + 2 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.

SpliceAI score
0.000 maximum delta

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

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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 · 17 not met · 0 not assessed · 6 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.333G>A (p.Val111=) is a synonymous variant in exon 1 of HTRA1, encoding HtrA serine peptidase 1.

This variant is ultra-rare in population databases: absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.56e-7 (1/1,524,404 alleles), satisfying PM2 at supporting strength.

Computational evidence supports a benign interpretation: REVEL score is 0.041 (well below the 0.5 pathogenic threshold), and SpliceAI predicts no splicing alteration (max delta = 0.00), meeting BP4 at supporting benign strength.

As a synonymous variant with no predicted splicing impact (SpliceAI max delta = 0.00) and low nucleotide conservation (REVEL = 0.041), this variant meets BP7 at supporting benign strength.

No functional studies, segregation data, de novo observations, case-control analyses, ClinVar classifications, or variant-specific publications are available for this variant. All other ACMG/AMP criteria are either not met or not applicable.

The evidence profile is conflicting: PM2_Supporting on the pathogenic side versus BP4_Supporting and BP7_Supporting on the benign side. Per the generic ACMG/AMP 2015 final classification rules (PMID:25741868), this constellation of conflicting supporting-level evidence is insufficient to reach a Likely Benign or Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 3

PM2 SupportingPM2 (absent or extremely low frequency in population databases) is met at supporting strength. NM_002775.4:c.333G>A is absent from gnomAD v2.1 and is present in gnomAD v4.1 at an allele frequency of 6.56e-7 (1/1,524,404 alleles), well below the generic ACMG PM2 threshold of 0.1%. It is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • gnomAD v4.1 total AF=6.56e-7 (1/1
  • 524
  • 404)
  • absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingBP4 (multiple lines of computational evidence suggest no impact on gene product) is met at supporting benign strength. REVEL score is 0.041, strongly favoring a benign interpretation (typical pathogenic threshold >0.5). SpliceAI max delta score is 0.00, predicting no splicing alteration. Together these indicate no computational evidence of a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL=0.041 (benign
  • far below 0.5 threshold)
  • SpliceAI max delta=0.00 (no splicing impact).
Still missing
  • BayesDel score unavailable
  • HCI prior not available for HTRA1.
Sources
revelspliceai ↗
BP7 SupportingBP7 (synonymous variant with no predicted splicing impact and nucleotide not highly conserved) is met at supporting benign strength. NM_002775.4:c.333G>A is a synonymous variant (p.Val111=). SpliceAI predicts no splicing alteration (max delta = 0.00). The low REVEL score (0.041) indicates the nucleotide position is not highly conserved across species. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Val111=)
  • SpliceAI max delta=0.00 (no splice impact)
  • REVEL=0.041 (nucleotide not conserved).
Sources
spliceai ↗revel

Not met · 17 · evaluated, threshold not reached

PS2 PS2 (de novo with confirmed paternity/maternity) is not met. No de novo observation of NM_002775.4:c.333G>A has been identified in ClinVar, the literature, or any evidence source in this case. Details ▾Hide ▴
Evidence considered
  • No de novo evidence available.
Still missing
  • No parental testing or de novo reports exist for this variant.
PS3 PS3 (well-established functional studies supporting a damaging effect) is not met. No functional assay data for NM_002775.4:c.333G>A was identified in ClinVar, the literature, or curated databases. OncoKB contains no functional annotation for this variant. Details ▾Hide ▴
Evidence considered
  • No functional data available for this variant.
Still missing
  • No in vitro or in vivo functional studies exist for this variant.
PS4 PS4 (prevalence in affected individuals significantly increased compared to controls) is not met. No case-control or cohort prevalence data for NM_002775.4:c.333G>A were identified. The variant is absent from ClinVar and no affected probands have been reported. Details ▾Hide ▴
Evidence considered
  • No affected proband or case-control data available.
Still missing
  • No case-control studies or cohort reports include this variant.
PM1 PM1 (located in a mutational hot spot or critical functional domain) is not met. Residue V111 does not lie in a statistically significant cancer hotspot, and no critical functional domain enrichment for pathogenic HTRA1 variants at this position has been established. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • exact variant not listed in hotspot database.
Still missing
  • No curated domain-level constraint data for HTRA1.
PM6 PM6 (de novo without confirmation of paternity/maternity) is not met. No de novo observation of NM_002775.4:c.333G>A has been reported in ClinVar or any literature source. Details ▾Hide ▴
Evidence considered
  • No de novo evidence available.
Still missing
  • No de novo reports exist for this variant.
PP1 PP1 (cosegregation with disease in multiple affected family members) is not met. No family segregation data for NM_002775.4:c.333G>A has been reported. Details ▾Hide ▴
Evidence considered
  • No cosegregation data available.
Still missing
  • No family studies or segregation analysis for this variant.
PP3 PP3 (multiple lines of computational evidence support a deleterious effect) is not met. REVEL score is 0.041 (benign-leaning; typical pathogenic threshold is >0.5). SpliceAI max delta score is 0.00 (no predicted splice impact). BayesDel score is unavailable. In silico evidence does not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL=0.041 (benign)
  • SpliceAI max delta=0.00 (no splice impact)
  • BayesDel unavailable.
Still missing
  • BayesDel score unavailable
  • HCI prior not available for HTRA1.
Sources
revelspliceai ↗
PP4 PP4 (patient phenotype or family history highly specific for the gene) is not met. No clinical phenotype data for individuals carrying NM_002775.4:c.333G>A is available in any evidence source. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data available.
Still missing
  • No clinical phenotype information for carriers of this variant.
PP5 PP5 (reputable source reports variant as pathogenic) is not met. NM_002775.4:c.333G>A is absent from ClinVar; no submitter has classified this variant. No publication reports it as pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no pathogenic classification from any source.
Sources
clinvar ↗
BA1 BA1 (allele frequency >1% in any population) is not met. The highest observed subpopulation frequency is in the Admixed American population at 0.00198% (1/50,538 alleles), far below the 1% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 maximum subpopulation AF=0.00198% (Admixed American)
  • well below 1%.
Sources
gnomad_v4 ↗
BS1 BS1 (allele frequency greater than expected for the disorder) is not met. The total allele frequency in gnomAD v4.1 is 6.56e-7 (0.0000656%), well below the generic ACMG BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 total AF=0.0000656%
  • well below 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BS2 BS2 (observed in a healthy adult individual in the homozygous state, or hemizygous in a male for an X-linked gene with full penetrance expected at an early age) is not met. No homozygotes for NM_002775.4:c.333G>A are reported in gnomAD. Details ▾Hide ▴
Evidence considered
  • Zero homozygotes in gnomAD v4.1.
Sources
gnomad_v4 ↗
BS3 BS3 (well-established functional studies show no damaging effect) is not met. No functional assay data for NM_002775.4:c.333G>A were identified. While REVEL and SpliceAI scores are consistent with a benign effect, these are in silico predictors and do not constitute well-established functional evidence. Details ▾Hide ▴
Evidence considered
  • No in vitro or in vivo functional data demonstrating no damaging effect.
Still missing
  • No functional studies (e.g.
  • protease activity assay
  • TGF-beta signaling readout) for this variant.
BS4 BS4 (lack of segregation with disease in affected family members) is not met. No family segregation data for NM_002775.4:c.333G>A is available. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family studies with this variant.
BP2 BP2 (observed in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant) is not met. No phase data or co-occurrence observations for NM_002775.4:c.333G>A with other HTRA1 variants are available. Details ▾Hide ▴
Evidence considered
  • No phase data or trans/cis observations available.
Still missing
  • No co-occurrence or phase data for this variant with other HTRA1 variants.
BP5 BP5 (variant found in a case with an alternate molecular basis for disease) is not met. No observation of NM_002775.4:c.333G>A in trans with, or co-occurring with, an alternate causative variant has been reported. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified in any carrier.
Still missing
  • No cases with alternate molecular diagnoses.
BP6 BP6 (reputable source reports variant as benign) is not met. NM_002775.4:c.333G>A is absent from ClinVar; no submitter has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_002775.4:c.333G>A is a synonymous variant (p.Val111=) that does not introduce a premature termination codon, disrupt a canonical splice site, or trigger nonsense-mediated decay. The variant falls into the 'other' bucket per ClinGen SVI PVS1 decision tree (PMC6185798) and is ineligible for generic PVS1 null-variant assessment. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Val111=) with no predicted null effect
  • ClinGen SVI PVS1 framework does not apply.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant. This synonymous variant (p.Val111=) does not alter the amino acid sequence; there is no amino acid change to compare against a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Synonymous variant produces no amino acid change
  • PS1 semantics do not apply.
PM5 N/APM5 requires a novel missense variant at the same residue as a pathogenic missense variant. NM_002775.4:c.333G>A is a synonymous variant (p.Val111=), not a missense change. PM5 candidate harvesting could not identify valid same-residue comparators. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • no missense residue context for PM5 comparator search.
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare. NM_002775.4:c.333G>A is a synonymous variant (p.Val111=), not a missense change. PP2 is not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • PP2 applies only to missense variants.
BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. NM_002775.4:c.333G>A is a synonymous variant (p.Val111=), not a missense change. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
  • Synonymous variant
  • BP1 applies only to missense variants.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion and is not defined in the generic ACMG framework applied here (PMID:25741868). No evidence supports invoking this criterion under any expanded framework. Details ▾Hide ▴
Evidence considered
  • Not a standard ACMG/AMP criterion
  • no framework definition applies.

Identifiers

Gene
HTRA1
Transcript
NM_002775.4
Coding (HGVS c.)
NM_002775.4:c.333G>A
Protein (HGVS p.)
NP_002766.1:p.(Val111=)
GRCh38
chr10:122461985 G>A
GRCh37
chr10:124221501 G>A

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 1 / 1,524,404 alleles AF 6.56e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 6.6e-07 · 1 / 1,524,404 alleles · 0 hom
Admixed American1 / 50,538 2e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.55994e-07; MAF= 0.00007%, 1/1524404 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.97871e-05; MAF= 0.00198%, 1/50538 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +355 bp
0.000
SpliceAI acceptor gainat +332 bp
0.000
SpliceAI donor lossat +139 bp
0.000
SpliceAI donor gainat +209 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.041
BayesDel
Not available

How the predictions were used

BP4 SupportingBP4 (multiple lines of computational evidence suggest no impact on gene product) is met at supporting benign strength. REVEL score is 0.041, strongly favoring a benign interpretation (typical pathogenic threshold >0.5). SpliceAI max delta score is 0.00, predicting no splicing alteration. Together these indicate no computational evidence of a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL=0.041 (benign
  • far below 0.5 threshold)
  • SpliceAI max delta=0.00 (no splicing impact).
Still missing
  • BayesDel score unavailable
  • HCI prior not available for HTRA1.
Sources
revelspliceai ↗
BP7 SupportingBP7 (synonymous variant with no predicted splicing impact and nucleotide not highly conserved) is met at supporting benign strength. NM_002775.4:c.333G>A is a synonymous variant (p.Val111=). SpliceAI predicts no splicing alteration (max delta = 0.00). The low REVEL score (0.041) indicates the nucleotide position is not highly conserved across species. Details ▾Hide ▴
Evidence considered
  • Synonymous variant p.(Val111=)
  • SpliceAI max delta=0.00 (no splice impact)
  • REVEL=0.041 (nucleotide not conserved).
Sources
spliceai ↗revel
PP3 PP3 (multiple lines of computational evidence support a deleterious effect) is not met. REVEL score is 0.041 (benign-leaning; typical pathogenic threshold is >0.5). SpliceAI max delta score is 0.00 (no predicted splice impact). BayesDel score is unavailable. In silico evidence does not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL=0.041 (benign)
  • SpliceAI max delta=0.00 (no splice impact)
  • BayesDel unavailable.
Still missing
  • BayesDel score unavailable
  • HCI prior not available for HTRA1.
Sources
revelspliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.041.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 1 / 1,524,404 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 Captured ClinVar source record 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= 6.55994e-07; MAF= 0.00007%, 1/1524404 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.97871e-05; MAF= 0.00198%, 1/50538 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.041.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.