rs41310207

Variant names:

• chr9-134795105-G-A
• rs41310207
• NM_000093.5:c.2724G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134795105-G-A
• chr9-134795105-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.2724G>A​(p.Pro908Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,304 control chromosomes in the GnomAD database, including 938 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. P908P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (67 hom., cov: 32)
  • Exomes 𝑓: 0.032 (871 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.41
• Publications: 6 publications found

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]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-134795105-G-A is Benign according to our data. Variant chr9-134795105-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.41 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0249 (3789/152282) while in subpopulation NFE AF = 0.0384 (2615/68014). AF 95% confidence interval is 0.0372. There are 67 homozygotes in GnomAd4. There are 1780 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3789 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2724G>A	p.Pro908Pro	synonymous_variant	Exon 33 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2724G>A	p.Pro908Pro	synonymous_variant	Exon 33 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.2724G>A	p.Pro908Pro	synonymous_variant	Exon 33 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2724G>A	p.Pro908Pro	synonymous_variant	Exon 33 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.2724G>A	p.Pro908Pro	synonymous_variant	Exon 33 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3793 AN: 152164 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00934

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0385

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0259 AC: 6485 AN: 250822 AF XY: 0.0260

Gnomad AFR exome AF: 0.00626

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0389

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0292

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0332

GnomAD4 exome AF: 0.0323 AC: 47125 AN: 1461022 Hom.: 871 Cov.: 40 AF XY: 0.0317 AC XY: 23031 AN XY: 726862

African (AFR) AF: 0.00618 AC: 207 AN: 33478

American (AMR) AF: 0.0159 AC: 710 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 1031 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00844 AC: 728 AN: 86256

European-Finnish (FIN) AF: 0.0294 AC: 1569 AN: 53330

Middle Eastern (MID) AF: 0.0293 AC: 169 AN: 5766

European-Non Finnish (NFE) AF: 0.0368 AC: 40864 AN: 1111280

Other (OTH) AF: 0.0306 AC: 1846 AN: 60360

GnomAD4 genome AF: 0.0249 AC: 3789 AN: 152282 Hom.: 67 Cov.: 32 AF XY: 0.0239 AC XY: 1780 AN XY: 74444

African (AFR) AF: 0.00669 AC: 278 AN: 41570

American (AMR) AF: 0.0220 AC: 337 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00934 AC: 45 AN: 4816

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10608

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0384 AC: 2615 AN: 68014

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0339 Hom.: 120

Bravo AF: 0.0237

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0402

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Mar 14, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The COL5A1 c.2724G>A (p.Pro908Pro) variant involves the alteration of a conserved nucleotide causing a synonymous change, which 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 3220/120556 (1/37, 68 homozygotes), which is approximately 21368 times the estimated maximal expected allele frequency for a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Therefore, the variant of interest has been classified as Benign. -

Nov 30, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Feb 06, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:1

Jul 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome type 7A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.20
DANN	Benign	0.70
PhyloP100		-2.4
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41310207; hg19: chr9-137686951; COSMIC: COSV107479200;