rs41310213

chr9-134782642-G-A

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.2431-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,611,960 control chromosomes in the GnomAD database, including 15,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2341 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12679 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.832

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=-0.98).
• BP6: Variant 9-134782642-G-A is Benign according to our data. Variant chr9-134782642-G-A is described in ClinVar as [Benign]. Clinvar id is 255062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134782642-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.2431-25G>A		intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.2431-25G>A		intron_variant
COL5A1	XM_017014266.3	c.2431-25G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.2431-25G>A		intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.2431-25G>A		intron_variant		2		A2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24632 AN: 152046 Hom.: 2338 Cov.: 33

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0729

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.167

GnomAD3 exomes AF: 0.130 AC: 32661 AN: 251096 Hom.: 2513 AF XY: 0.126 AC XY: 17152 AN XY: 135820

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.0747

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.0782

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.128 AC: 186228 AN: 1459796 Hom.: 12679 Cov.: 31 AF XY: 0.126 AC XY: 91468 AN XY: 726368

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.0787

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.0774

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.162 AC: 24655 AN: 152164 Hom.: 2341 Cov.: 33 AF XY: 0.159 AC XY: 11803 AN XY: 74394

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.0998

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.0726

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.165

Alfa AF: 0.141 Hom.: 304

Bravo AF: 0.164

Asia WGS AF: 0.135 AC: 472 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
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.2431-25G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing while ESE finder predicts the loss of a SRp40 binding motif. However, these predictions have yet to be confirmed by functional studies. This variant was found in 16316/120916 control chromosomes (1295 homozygotes) at a frequency of 0.1349367, which is approximately 107949 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory and one reputable database classified this variant as benign. Taken together, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	4.3
Dann	Benign	0.49

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: rs41310213; hg19: chr9-137674488; COSMIC: COSV65667083;