rs149616140
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000093.5(COL5A1):c.3418G>A(p.Val1140Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,607,406 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.3418G>A | p.Val1140Met | missense_variant | Exon 43 of 66 | ENST00000371817.8 | NP_000084.3 | |
COL5A1 | NM_001278074.1 | c.3418G>A | p.Val1140Met | missense_variant | Exon 43 of 66 | NP_001265003.1 | ||
COL5A1 | XM_017014266.3 | c.3418G>A | p.Val1140Met | missense_variant | Exon 43 of 65 | XP_016869755.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.3418G>A | p.Val1140Met | missense_variant | Exon 43 of 66 | 1 | NM_000093.5 | ENSP00000360882.3 | ||
COL5A1 | ENST00000371820.4 | c.3418G>A | p.Val1140Met | missense_variant | Exon 43 of 66 | 2 | ENSP00000360885.4 | |||
COL5A1 | ENST00000463925.1 | n.274G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000847 AC: 129AN: 152250Hom.: 4 Cov.: 33
GnomAD3 exomes AF: 0.000409 AC: 95AN: 232178Hom.: 0 AF XY: 0.000395 AC XY: 50AN XY: 126528
GnomAD4 exome AF: 0.000267 AC: 389AN: 1455038Hom.: 0 Cov.: 31 AF XY: 0.000253 AC XY: 183AN XY: 723134
GnomAD4 genome AF: 0.000847 AC: 129AN: 152368Hom.: 4 Cov.: 33 AF XY: 0.000805 AC XY: 60AN XY: 74520
ClinVar
Submissions by phenotype
not provided Benign:2
This variant is associated with the following publications: (PMID: 30858776) -
COL5A1: BS1, BS2 -
Ehlers-Danlos syndrome Uncertain:1
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not specified Benign:1
Variant summary: COL5A1 c.3418G>A (p.Val1140Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 232178 control chromosomes. The observed variant frequency is approximately 13.093 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is benign. c.3418G>A has been reported in the literature in at least two related individuals affected with clinical features of Ehlers-Danlos Syndrome (e.g., Junkiert-Czarnecka_2019), however these report(s) do not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30858776). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; one submitter classified the variant as a variant of uncertain significance, while four submitters classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
COL5A1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Ehlers-Danlos syndrome, classic type, 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at