rs2228560

Variant names:

• chr9-134820151-G-A
• rs2228560
• NM_000093.5:c.4482G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-134820151-G-A
• chr9-134820151-G-C
• chr9-134820151-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.Pro1494Pro) 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:14
• 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 rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 65		XP_016869755.1
LOC101448202	NR_103451.2	n.129C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4482G>A	p.Pro1494Pro	synonymous_variant	Exon 58 of 66	2		ENSP00000360885.4

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Nov 12, 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. -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 15, 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.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. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

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

Sep 29, 2016

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 16, 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	-0.76
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;