rs12685946

Positions:

• chr9-134750632-A-G

Variant summary

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

The ENST00000371817.8(COL5A1):​c.1569+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,612,112 control chromosomes in the GnomAD database, including 49,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7388 hom., cov: 32)
  • Exomes 𝑓: 0.23 (42588 hom.)
• Consequence: COL5A1 ENST00000371817.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.73

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=-0.94).
• BP6: Variant 9-134750632-A-G is Benign according to our data. Variant chr9-134750632-A-G is described in ClinVar as [Benign]. Clinvar id is 136862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134750632-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1569+16A>G		intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1569+16A>G		intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.1569+16A>G		intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1569+16A>G		intron_variant		1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.1569+16A>G		intron_variant		2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44030 AN: 151898 Hom.: 7381 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.243

GnomAD3 exomes AF: 0.228 AC: 57228 AN: 250686 Hom.: 7576 AF XY: 0.223 AC XY: 30313 AN XY: 135758

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.346

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.235 AC: 342867 AN: 1460096 Hom.: 42588 Cov.: 33 AF XY: 0.232 AC XY: 168366 AN XY: 726440

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.325

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.231

Gnomad4 NFE exome AF: 0.236

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.290 AC: 44064 AN: 152016 Hom.: 7388 Cov.: 32 AF XY: 0.285 AC XY: 21218 AN XY: 74330

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.240

Alfa AF: 0.240 Hom.: 916

Bravo AF: 0.298

Asia WGS AF: 0.216 AC: 752 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0020
DANN	Benign	0.19

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: rs12685946; hg19: chr9-137642478; COSMIC: COSV65671897;