rs3124932

Positions:

• chr9-134780166-C-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:8
• 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/exons	MANE	UniProt
COL5A1	NM_000093.5	c.2430+20C>T		intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.2430+20C>T		intron_variant
COL5A1	XM_017014266.3	c.2430+20C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.2430+20C>T		intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.2430+20C>T		intron_variant		2		A2

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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

Jul 30, 2021

- -

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.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. -

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;