rs45497895

Positions:

• chr9-134785950-G-A
• chr9-134785950-G-C
• chr9-134785950-G-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.2593-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,555,858 control chromosomes in the GnomAD database, including 3,126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (714 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2412 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.131

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=-0.89).
• BP6: Variant 9-134785950-G-A is Benign according to our data. Variant chr9-134785950-G-A is described in ClinVar as [Benign]. Clinvar id is 255066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.2593-45G>A		intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2593-45G>A		intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.2593-45G>A		intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2593-45G>A		intron_variant		1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.2593-45G>A		intron_variant		2		ENSP00000360885	A2

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12090 AN: 152104 Hom.: 714 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0309

Gnomad FIN AF: 0.0556

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0689

GnomAD3 exomes AF: 0.0569 AC: 13727 AN: 241424 Hom.: 561 AF XY: 0.0536 AC XY: 7012 AN XY: 130722

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0581

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.0333

Gnomad FIN exome AF: 0.0592

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0487

GnomAD4 exome AF: 0.0530 AC: 74404 AN: 1403636 Hom.: 2412 Cov.: 25 AF XY: 0.0522 AC XY: 36621 AN XY: 701322

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.0567

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0602

GnomAD4 genome AF: 0.0795 AC: 12100 AN: 152222 Hom.: 714 Cov.: 33 AF XY: 0.0771 AC XY: 5740 AN XY: 74440

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0303

Gnomad4 FIN AF: 0.0556

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0295 Hom.: 20

Bravo AF: 0.0821

Asia WGS AF: 0.0790 AC: 276 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 14, 2018	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.89
CADD	Benign	0.41
DANN	Benign	0.82

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: rs45497895; hg19: chr9-137677796; COSMIC: COSV65664826;