rs962170388

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000093.5(COL5A1):​c.1291G>A​(p.Gly431Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000308 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

3
12
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.89
Variant links:
Genes affected
COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.813
BS2
High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL5A1NM_000093.5 linkc.1291G>A p.Gly431Arg missense_variant Exon 8 of 66 ENST00000371817.8 NP_000084.3 P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1NM_001278074.1 linkc.1291G>A p.Gly431Arg missense_variant Exon 8 of 66 NP_001265003.1 B2ZZ86Q59EE7
COL5A1XM_017014266.3 linkc.1291G>A p.Gly431Arg missense_variant Exon 8 of 65 XP_016869755.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL5A1ENST00000371817.8 linkc.1291G>A p.Gly431Arg missense_variant Exon 8 of 66 1 NM_000093.5 ENSP00000360882.3 P20908-1
COL5A1ENST00000371820.4 linkc.1291G>A p.Gly431Arg missense_variant Exon 8 of 66 2 ENSP00000360885.4 P20908-2H7BY82
COL5A1ENST00000469093.1 linkn.30G>A non_coding_transcript_exon_variant Exon 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248882
Hom.:
0
AF XY:
0.00000742
AC XY:
1
AN XY:
134748
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000898
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000308
AC:
45
AN:
1461782
Hom.:
0
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
34
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000340
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jul 22, 2021
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 459654; Landrum et al., 2016) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Sep 13, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.G431R variant (also known as c.1291G>A), located in coding exon 8 of the COL5A1 gene, results from a G to A substitution at nucleotide position 1291. The glycine at codon 431 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a coronary artery dissection cohort and in a high myopia cohort (Zekavat SM et al. JAMA Cardiol, 2022 Apr;7:396-406; Liu Y et al. Sci Rep, 2023 Oct;13:18347). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Ehlers-Danlos syndrome, classic type Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1
Dec 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Uncertain
0.028
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Uncertain
0.55
D;.
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.15
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Uncertain
2.2
M;M
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-3.5
D;.
REVEL
Uncertain
0.56
Sift
Benign
0.11
T;.
Sift4G
Uncertain
0.039
D;D
Polyphen
1.0
D;.
Vest4
0.84
MutPred
0.25
Loss of glycosylation at S428 (P = 0.096);Loss of glycosylation at S428 (P = 0.096);
MVP
0.85
MPC
0.70
ClinPred
0.70
D
GERP RS
4.1
Varity_R
0.14
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs962170388; hg19: chr9-137623468; COSMIC: COSV65672645; API