rs2228560

chr9-134820151-G-Achr9-134820151-G-Cchr9-134820151-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000093.5(COL5A1):c.4482G>A(p.Pro1494=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,613,790 control chromosomes in the GnomAD database, including 2,116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1494P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.039 (156 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1960 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -4.64

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]

LOC101448202 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-134820151-G-A is Benign according to our data. Variant chr9-134820151-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134820151-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.4482G>A	p.Pro1494=	synonymous_variant	58/66	ENST00000371817.8
LOC101448202	NR_103451.2	n.129C>T		non_coding_transcript_exon_variant	2/2
COL5A1	NM_001278074.1	c.4482G>A	p.Pro1494=	synonymous_variant	58/66
COL5A1	XM_017014266.3	c.4482G>A	p.Pro1494=	synonymous_variant	58/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.4482G>A	p.Pro1494=	synonymous_variant	58/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.4482G>A	p.Pro1494=	synonymous_variant	58/66	2		A2

Frequencies

GnomAD3 genomes AF: 0.0392 AC: 5969 AN: 152078 Hom.: 156 Cov.: 33

Gnomad AFR AF: 0.00925

Gnomad AMI AF: 0.0386

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0418 AC: 10509 AN: 251342 Hom.: 312 AF XY: 0.0421 AC XY: 5720 AN XY: 135874

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0438

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0591

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0493 AC: 72083 AN: 1461594 Hom.: 1960 Cov.: 47 AF XY: 0.0487 AC XY: 35381 AN XY: 727102

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.0223

Gnomad4 ASJ exome AF: 0.0440

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.0737

Gnomad4 NFE exome AF: 0.0550

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0392 AC: 5967 AN: 152196 Hom.: 156 Cov.: 33 AF XY: 0.0391 AC XY: 2910 AN XY: 74402

Gnomad4 AFR AF: 0.00922

Gnomad4 AMR AF: 0.0320

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.0753

Gnomad4 NFE AF: 0.0575

Gnomad4 OTH AF: 0.0365

Alfa AF: 0.0493 Hom.: 1213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -

Ehlers-Danlos syndrome, classic type, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2016

This alteration is classified as 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 type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 15, 2017

Variant summary: The COL5A1 c.4482G>A (p.Pro1494Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools suggest on a creation of a new cryptic donor-accepter pair. ESE finder predicts that this variant may eliminate an SF2/ASF ESE site at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 5251/121210 control chromosomes (182 homozygotes) at a frequency of 0.0433215, which is approximately 34657 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. The variant has been cited in at least one publication and was described by the authors as a common polymorphism (Symoens_HM_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.6
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs2228560; hg19: chr9-137711997; COSMIC: COSV65665652; COSMIC: COSV65665652;