rs3124932

Variant names:

• chr9-134780166-C-T
• rs3124932
• NM_000093.5:c.2430+20C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.2430+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,611,542 control chromosomes in the GnomAD database, including 163,758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12189 hom., cov: 33)
  • Exomes 𝑓: 0.45 (151569 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.76

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 9-134780166-C-T is Benign according to our data. Variant chr9-134780166-C-T is described in ClinVar as [Benign]. Clinvar id is 136866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134780166-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2430+20C>T		intron_variant	Intron 28 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2430+20C>T		intron_variant	Intron 28 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.2430+20C>T		intron_variant	Intron 28 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2430+20C>T		intron_variant	Intron 28 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.2430+20C>T		intron_variant	Intron 28 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55888 AN: 151986 Hom.: 12184 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.0810

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.401

GnomAD3 exomes AF: 0.418 AC: 104628 AN: 250528 Hom.: 24214 AF XY: 0.426 AC XY: 57849 AN XY: 135712

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.0660

Gnomad SAS exome AF: 0.457

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.461

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.447 AC: 651994 AN: 1459438 Hom.: 151569 Cov.: 39 AF XY: 0.448 AC XY: 325358 AN XY: 726128

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.485

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.0743

Gnomad4 SAS exome AF: 0.459

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.465

Gnomad4 OTH exome AF: 0.424

GnomAD4 genome AF: 0.368 AC: 55900 AN: 152104 Hom.: 12189 Cov.: 33 AF XY: 0.371 AC XY: 27607 AN XY: 74340

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.487

Gnomad4 ASJ AF: 0.495

Gnomad4 EAS AF: 0.0803

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.489

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.406

Alfa AF: 0.450 Hom.: 22445

Bravo AF: 0.358

Asia WGS AF: 0.275 AC: 956 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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.2430+20C>T variant involves the alteration of a non-conserved intronic nucleotide. Although Mutation Taster was down at the time of this scoring, 5/5 splice prediction tools predict no significant impact on normal splicing and has no significant effect on ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 49278/120530 control chromosomes (11250 homozygotes) at a frequency of 0.4088443, which is approximately 327075 times the estimated maximal expected allele frequency of 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. Taken together, this variant is classified as benign. -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: 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	-0.96
CADD	Benign	0.040
DANN	Benign	0.58

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

Other links and lift over

dbSNP: rs3124932; hg19: chr9-137672012; COSMIC: COSV65666833;