COL4A1c.343G>AUncertain significance

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Variant interpretation report

COL4A1 c.343G>A, p.(Gly115Ser)

NM_001845.5:c.343G>A NP_001836.3:p.(Gly115Ser) 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 COL4A1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 5 Uncertain significance · 1 Likely pathogenic
Pipeline record: 15 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PM1 (moderate): The variant substitutes Gly115 in the collagen triple-helical domain (Gly-X-Y repeat region). Glycine residues in the collagen triple-helical domain are structurally essential for proper helix formation; glycine substitutions in this domain are a well-established pathogenic mechanism across all collagen genes, including COL4A1. This residue lies within a critical functional domain where pathogenic missense variants cluster and benign variation is extremely rare. The COL4A1/COL4A2 clinical spectrum literature (PMID:25719457) confirms a high density of pathogenic mutations in this domain.
PM2 (supporting): The variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00177% (5/282,856 alleles, 0 homozygotes), gnomAD v4.1 allele frequency is 0.00192% (31/1,613,960 alleles, 0 homozygotes), and it is absent from gnomAD-Canada v1.0. All frequencies are well below the 0.1% PM2 threshold. The highest subpopulation frequency is 0.00310% in European (non-Finnish) in v2.1 and 0.00267% in African/African American in v4.1.
PP3 (supporting): Multiple in silico predictors support a deleterious effect of this missense variant. REVEL score is 0.963 (highly pathogenic-leaning, well above the 0.5 threshold). BayesDel score is 0.571 (damaging, above the 0.5 threshold). SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a deep exonic missense variant. The combination of REVEL and BayesDel scores provides supporting evidence for pathogenicity.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PM1Moderate

PM1 · moderate

The variant substitutes Gly115 in the collagen triple-helical domain (Gly-X-Y repeat region). Glycine residues in the collagen triple-helical domain are structurally essential for proper helix formation; glycine substitutions in this domain are a well-established pathogenic mechanism across all collagen genes, including COL4A1. This residue lies within a critical functional domain where pathogenic missense variants cluster and benign variation is extremely rare. The COL4A1/COL4A2 clinical spectrum literature (PMID:25719457) confirms a high density of pathogenic mutations in this domain.

PM2Supporting

PM2 · supporting

The variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00177% (5/282,856 alleles, 0 homozygotes), gnomAD v4.1 allele frequency is 0.00192% (31/1,613,960 alleles, 0 homozygotes), and it is absent from gnomAD-Canada v1.0. All frequencies are well below the 0.1% PM2 threshold. The highest subpopulation frequency is 0.00310% in European (non-Finnish) in v2.1 and 0.00267% in African/African American in v4.1.

PP3Supporting

PP3 · supporting

Multiple in silico predictors support a deleterious effect of this missense variant. REVEL score is 0.963 (highly pathogenic-leaning, well above the 0.5 threshold). BayesDel score is 0.571 (damaging, above the 0.5 threshold). SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a deep exonic missense variant. The combination of REVEL and BayesDel scores provides supporting evidence for pathogenicity.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 supporting, which maps to VUS.

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

31 / 1,613,960 alleles

gnomAD v4.1: 31 / 1,613,960 alleles. Recorded AF 1.92074e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.76768e-05; MAF= 0.00177%, 5/282856 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.09674e-05; MAF= 0.00310%, 4/129168 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

6 reported laboratory submissions

5 Uncertain significance · 1 Likely pathogenic.

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; COSV65433356, 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 · 17 not met · 3 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_001845.5:c.343G>A (p.Gly115Ser) is a missense variant in COL4A1 affecting a glycine residue in the collagen triple-helical Gly-X-Y repeat domain.

The variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00177% (5/282,856 alleles) and gnomAD v4.1 allele frequency is 0.00192% (31/1,613,960 alleles), both well below the 0.1% PM2 threshold. It is absent from gnomAD-Canada.

Gly115 lies within the collagen triple-helical domain, a critical functional domain where glycine substitutions are a well-established pathogenic mechanism across collagen genes and specifically in COL4A1-related disorders (PMID:25719457). This supports application of PM1 at moderate strength.

In silico predictors support a deleterious effect: REVEL score 0.963 (highly pathogenic-leaning) and BayesDel score 0.571 (damaging), meeting PP3 at supporting strength.

In ClinVar (ID 2158622), this variant has been reported as Uncertain significance by 5 clinical laboratories and as Likely pathogenic by 1 clinical laboratory (Labcorp Genetics). No expert panel review is available.

Exploratory evidence recovery suggests potential functional evidence of impaired collagen IV secretion (PMID:15905400) and a possible de novo observation, but these could not be independently verified from available abstracts and require human review of full-text publications.

Applying generic ACMG/AMP 2015 criteria: PM1 (moderate) + PM2 (supporting) + PP3 (supporting) = 1 moderate + 2 supporting, which does not reach the Likely Pathogenic threshold (requires ≥2 moderate OR ≥4 supporting OR 1 strong + ≥2 supporting). The classification is Variant of Uncertain Significance. Additional evidence (PS3 functional confirmation, PM6 de novo verification) could upgrade this to Likely Pathogenic.

Met · 3

PM1 ModerateThe variant substitutes Gly115 in the collagen triple-helical domain (Gly-X-Y repeat region). Glycine residues in the collagen triple-helical domain are structurally essential for proper helix formation; glycine substitutions in this domain are a well-established pathogenic mechanism across all collagen genes, including COL4A1. This residue lies within a critical functional domain where pathogenic missense variants cluster and benign variation is extremely rare. The COL4A1/COL4A2 clinical spectrum literature (PMID:25719457) confirms a high density of pathogenic mutations in this domain. Details ▾Hide ▴

Evidence considered

Gly115 is a glycine residue within the collagen triple-helical Gly-X-Y repeat domain
a well-established critical functional domain
glycine substitutions in collagen triple-helical domains are a classic pathogenic mechanism
PMID:25719457 describes 21 COL4A1 mutations concentrated in the triple-helical domain associated with porencephaly and cerebrovascular disease

Still missing

COL4A1-specific regional missense constraint metrics (gnomAD missense Z-score for the triple-helical domain) would strengthen this assessment

Sources

25719457

PM2 SupportingThe variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00177% (5/282,856 alleles, 0 homozygotes), gnomAD v4.1 allele frequency is 0.00192% (31/1,613,960 alleles, 0 homozygotes), and it is absent from gnomAD-Canada v1.0. All frequencies are well below the 0.1% PM2 threshold. The highest subpopulation frequency is 0.00310% in European (non-Finnish) in v2.1 and 0.00267% in African/African American in v4.1. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 5/282
856 (AF=0.00177%)
grpmax FAF=7.01e-06
gnomAD v4.1: 31/1
613
960 (AF=0.00192%)
grpmax FAF=1.567e-05
gnomAD-Canada: absent
all frequencies << 0.1% PM2 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 SupportingMultiple in silico predictors support a deleterious effect of this missense variant. REVEL score is 0.963 (highly pathogenic-leaning, well above the 0.5 threshold). BayesDel score is 0.571 (damaging, above the 0.5 threshold). SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for a deep exonic missense variant. The combination of REVEL and BayesDel scores provides supporting evidence for pathogenicity. Details ▾Hide ▴

Evidence considered

REVEL: 0.963 (pathogenic-leaning)
BayesDel: 0.571 (damaging)
SpliceAI delta max: 0.01 (no splice impact)

Sources

revelbayesdelspliceai ↗

Not met · 17 · evaluated, threshold not reached

PS1 No alternative nucleotide change at codon 343 producing the same amino acid substitution (Gly115Ser) with a known pathogenic classification was identified in ClinVar or the literature. PS1 requires a different nucleotide change at the same codon resulting in the same missense change that has been established as pathogenic. Details ▾Hide ▴

Evidence considered

No same-amino-acid alternative nucleotide variants identified at codon 343

Still missing

Systematic search for alternate nucleotide changes at codon 343 producing Gly115Ser

PS4 The variant is present in ClinVar (ID 2158622) with multiple submissions from clinical laboratories, but no statistically significant enrichment (odds ratio) in affected individuals versus the general population has been computed. PS4 requires demonstration that the variant prevalence in cases significantly exceeds that in controls. The variant is also present in gnomAD at very low frequency (v2.1: 5/282,856; v4.1: 31/1,613,960), which would factor into an enrichment analysis. Details ▾Hide ▴

Evidence considered

ClinVar: 6 submissions (5 VUS
1 LP) for porencephaly/cerebral small vessel disease
no case-control enrichment statistics available
gnomAD baseline frequency ~0.002%

Still missing

Formal case-control enrichment analysis (number of affected probands vs gnomAD frequency)
systematic literature review for all reported probands

Sources

clinvar ↗gnomad_v2 ↗gnomad_v4 ↗

PP1 No evidence of cosegregation of this variant with disease in multiple affected family members has been identified. The variant was reported as a de novo event in the index case (exploratory evidence, unverified), precluding cosegregation analysis from that family. No additional families with this variant and multiple affected members have been reported. Details ▾Hide ▴

Evidence considered

No cosegregation data available
variant reported as de novo (single case)

Still missing

Literature search for familial reports of NM_001845.5:c.343G>A with cosegregation data

PP2 PP2 is applicable when a missense variant occurs in a gene with a low rate of benign missense variation and where pathogenic missense variants are a common mechanism. While COL4A1-related disorders are known to be caused by missense variants (particularly glycine substitutions), no specific COL4A1 missense constraint data (e.g., gnomAD missense Z-score, regional constraint metrics) was provided in the case evidence to support PP2 application. Details ▾Hide ▴

Evidence considered

No COL4A1-specific missense constraint metrics provided in case evidence

Still missing

COL4A1 gnomAD missense Z-score and o/e ratio
regional constraint data for the triple-helical domain

PP4 No patient phenotype or family history information was provided in the case summary. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴

Evidence considered

No patient phenotype or clinical data provided in case summary

Still missing

Patient phenotype data
family history information
clinical indication for testing

PP5 PP5 requires that a reputable source (e.g., clinical laboratory, expert panel) has recently reported the variant as pathogenic with the supporting evidence not available for independent evaluation. In ClinVar, 5 of 6 clinical laboratories classify this variant as Uncertain significance, with only 1 (Labcorp Genetics) classifying as Likely pathogenic. The majority classification is VUS, and no expert panel has reviewed this variant. This does not meet the PP5 threshold. Details ▾Hide ▴

Evidence considered

ClinVar: 5 VUS
1 LP
no expert panel review
majority classification is uncertain

Sources

clinvar ↗

BA1 The variant allele frequency in gnomAD is approximately 0.002% (v2.1: 0.00177%, v4.1: 0.00192%), far below the BA1 threshold of >1%. This criterion is clearly not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF: 0.00177% << 1%
gnomAD v4.1 AF: 0.00192% << 1%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The variant allele frequency in gnomAD is approximately 0.002% (v2.1: 0.00177%, v4.1: 0.00192%), well below the BS1 threshold of >0.3%. This variant is too rare in population databases to meet BS1. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF: 0.00177% << 0.3%
gnomAD v4.1 AF: 0.00192% << 0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No evidence that this variant has been observed in healthy adult individuals for whom COL4A1-related disorders would be expected to manifest with full penetrance at an early age. The variant's extreme rarity in population databases and absence of homozygous observations are inconsistent with a benign variant observed in healthy adults. Details ▾Hide ▴

Evidence considered

No reports of this variant in healthy adults
gnomAD shows extreme rarity with no homozygotes

BS3 BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. The available evidence points in the opposite direction: exploratory evidence (PMID:15905400, unverified) suggests impaired collagen IV secretion, and in silico predictors (REVEL 0.963, BayesDel 0.571) support a deleterious effect. No studies suggest a benign functional impact. Details ▾Hide ▴

Evidence considered

No evidence of benign functional impact
all available evidence suggests deleterious effect

BS4 No evidence of non-segregation with disease has been identified. No reports exist of this variant being present in unaffected family members while absent from affected members in the same family. The variant's extreme rarity and reported association with disease (ClinVar LP submission, exploratory de novo report) are inconsistent with BS4. Details ▾Hide ▴

Evidence considered

No non-segregation data reported
variant is too rare to expect incidental observation in unaffected controls

BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. COL4A1-related disorders (porencephaly, cerebral small vessel disease, HANAC syndrome) are well-established to be caused by missense variants, particularly glycine substitutions in the triple-helical domain. The disease mechanism is primarily dominant-negative, not haploinsufficiency. BP1 is clearly not applicable. Details ▾Hide ▴

Evidence considered

COL4A1-related disorders are caused by missense variants (dominant-negative mechanism)
glycine substitutions in COL4A1 are a known pathogenic mechanism

BP2 BP2 applies when a variant is observed in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such observations have been reported for this variant. COL4A1 disorders are autosomal dominant, and observation in trans with another pathogenic COL4A1 allele would not be expected. Details ▾Hide ▴

Evidence considered

No reports of this variant in trans or cis with another pathogenic COL4A1 variant

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score is 0.963 (highly pathogenic-leaning) and BayesDel is 0.571 (damaging), both predicting a deleterious effect, not a benign one. SpliceAI delta max of 0.01 predicts no splice impact, but this alone is insufficient to offset the strong pathogenic predictions from missense-specific tools. Details ▾Hide ▴

Evidence considered

REVEL: 0.963 (deleterious)
BayesDel: 0.571 (damaging)
SpliceAI: 0.01 (no splice impact but missense predictors strongly suggest pathogenicity)

Sources

revelbayesdelspliceai ↗

BP5 BP5 requires that a reputable source has recently reported the variant as benign with the supporting evidence not available for independent evaluation. No clinical laboratory or expert panel has classified this variant as benign or likely benign. All ClinVar submissions classify as VUS or LP. Details ▾Hide ▴

Evidence considered

No benign or likely benign classifications in ClinVar (all VUS or LP)

Sources

clinvar ↗

BP6 BP6 requires that a reputable source has recently reported the variant as benign with the supporting evidence available for independent evaluation. No reputable source has classified this variant as benign. All ClinVar classifications are VUS or LP. Details ▾Hide ▴

Evidence considered

No benign classifications from any reputable source
all classifications are VUS or LP

Sources

clinvar ↗

PS5 ClinVar has one Likely pathogenic submission (Labcorp Genetics, SCV003470144) among six total submissions, with five clinical laboratories classifying as Uncertain significance. PS5 requires a reputable source to have recently reported the variant as pathogenic with the supporting evidence being unavailable for independent evaluation. A single LP submission against a majority VUS classification does not meet this threshold. Details ▾Hide ▴

Evidence considered

ClinVar: 1 LP (Labcorp) vs 5 VUS
no expert panel classification

Sources

clinvar ↗

Not assessed · 3 · no assessment recorded

PS2 Exploratory evidence recovery suggests a de novo observation of this variant in a proband with porencephaly (Gould et al., 2005, PMID:15905400), but maternity/paternity was not confirmed and the variant-specific de novo observation could not be independently verified from the PubMed abstract. If confirmed with paternity testing, this would qualify as PS2. Without paternity confirmation, it falls to PM6_supporting. Details ▾Hide ▴

Evidence considered

Exploratory sub-agent reported de novo observation in proband with porencephaly
paternity not confirmed
variant-specific claim unverifiable from abstract alone

Still missing

Confirm de novo observation from PMID:15905400 full text
verify paternity/maternity confirmation status

Sources

15905400

PS3 Exploratory evidence recovery suggests functional studies in HEK293 cells showed intracellular accumulation and impaired collagen IV secretion for the p.Gly115Ser mutant (PMID:15905400), demonstrating a dominant-negative effect. However, the variant-specific functional data could not be independently verified from the PubMed abstract alone. If confirmed from full text, this well-established assay supports PS3_supporting. Details ▾Hide ▴

Evidence considered

Exploratory sub-agent reported functional evidence: impaired secretion and intracellular accumulation of collagen IV in HEK293 cells for p.Gly115Ser
unverifiable from abstract

Still missing

Verify functional assay data for p.Gly115Ser in full text of PMID:15905400
assess whether additional independent functional studies exist

Sources

15905400

PM6 Exploratory evidence recovery reports that a proband with porencephaly was heterozygous for c.343G>A with both parents wild-type (PMID:15905400, Gould et al. 2005). Paternity/maternity was not confirmed, placing this observation in the PM6 (assumed de novo) category. However, variant-specific confirmation could not be obtained from the PubMed abstract alone. If verified from full text, this qualifies as PM6_supporting. Details ▾Hide ▴

Evidence considered

Exploratory sub-agent reported de novo observation without paternity confirmation
variant-specific claim not independently verifiable from abstract

Still missing

Confirm de novo observation for c.343G>A from full text of PMID:15905400
verify parental genotypes
assess whether any subsequent studies confirmed this de novo event

Sources

15905400

Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site). NM_001845.5:c.343G>A is a missense variant (p.Gly115Ser) and does not qualify for any PVS1 strength tier under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴

Evidence considered

Variant is a substitution
not a null variant
pvs1_variant_assessment bucket: other

Sources

pvs1_generic_framework ↗

PM5 N/APM5 requires a different pathogenic missense variant at the same amino acid residue. No same-residue comparator variants at Gly115 were identified in ClinVar or the literature. The PM5 candidate harvest returned zero candidates at this residue. Details ▾Hide ▴

Evidence considered

No alternative pathogenic missense variants identified at residue 115 (Gly115)

BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact to the splice site consensus sequence nor creation of a new splice site. NM_001845.5:c.343G>A is a missense variant (p.Gly115Ser), not a synonymous variant. BP7 is not applicable. Details ▾Hide ▴

Evidence considered

Variant is a missense substitution
not a synonymous variant

Identifiers

Gene: COL4A1
Transcript: NM_001845.5
Coding (HGVS c.): NM_001845.5:c.343G>A
Protein (HGVS p.): NP_001836.3:p.(Gly115Ser)
GRCh38: chr13:110212461 C>T
GRCh37: chr13:110864808 C>T
ClinVar: 2158622
COSMIC: COSV65433356

Gene diagram

Every interpreted variant in COL4A1, mapped onto the exon structure of NM_001845.5. Select a row to find it on the plot.

COL4A1NM_001845.5

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in COL4A1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 31 / 1,613,960 alleles AF 1.92e-05 · 0 homozygotes · FAF 1.57e-05

gnomAD v2.1 5 / 282,856 alleles AF 1.77e-05 · 0 homozygotes · FAF 7.01e-06

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 1.9e-05 · 31 / 1,613,960 alleles · 0 hom · FAF 1.6e-05

African/African American2 / 74,868	2.7e-05
European (non-Finnish)27 / 1,180,042	2.3e-05
Admixed American1 / 59,992	1.7e-05
Remaining individuals1 / 62,482	1.6e-05

0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 1.8e-05 · 5 / 282,856 alleles · 0 hom · FAF 7e-06

European (non-Finnish)4 / 129,168	3.1e-05
Admixed American1 / 35,440	2.8e-05

0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.92074e-05; MAF= 0.00192%, 31/1613960 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67137e-05; MAF= 0.00267%, 2/74868 alleles, homozygotes = 0); grpmax FAF= 1.567e-05.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp

0.000

SpliceAI acceptor gainat -2 bp

0.000

SpliceAI donor lossat +417 bp

0.000

SpliceAI donor gainat -18 bp

0.010

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.010

Other predictors

REVEL: 0.963
BayesDel: 0.571

How the predictions were used

Evidence considered

REVEL: 0.963 (pathogenic-leaning)
BayesDel: 0.571 (damaging)
SpliceAI delta max: 0.01 (no splice impact)

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.963 (deleterious)
BayesDel: 0.571 (damaging)
SpliceAI: 0.01 (no splice impact but missense predictors strongly suggest pathogenicity)

Sources

revelbayesdelspliceai ↗

Evidence considered

Variant is a missense substitution
not a synonymous variant

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.963. BayesDel score = 0.571004.

10 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

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.

Marini JC et al. · 2007

No paper-specific finding is recorded.

PMID 17078022 ↗
Collagen structure and stability.

Shoulders MD et al. · 2009

No paper-specific finding is recorded.

PMID 19344236 ↗
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.

Richards S et al. · 2015

No paper-specific finding is recorded.

PMID 25741868 ↗
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Long CG et al. · 1993

No paper-specific finding is recorded.

PMID 8218237 ↗
Alport Syndrome.

Adam MP et al. · 1993

No paper-specific finding is recorded.

PMID 20301386 ↗
COL4A1-Related Disorders.

Adam MP et al. · 1993

No paper-specific finding is recorded.

PMID 20301768 ↗
The human type I collagen mutation database.

Dalgleish R · 1997

No paper-specific finding is recorded.

PMID 9016532 ↗
Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association.

Meschia JF et al. · 2014

No paper-specific finding is recorded.

PMID 25355838 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

No paper-specific finding is recorded.

PMID 28492532 ↗
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

Bella J et al. · 1994

No paper-specific finding is recorded.

PMID 7695699 ↗

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

gnomAD v4.1 31 / 1,613,960 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 5 Uncertain significance · 1 Likely pathogenic 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

gnomAD v2.1

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 2158622)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.963. BayesDel score = 0.571004.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV65433356, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.