rs3128598

Positions:

• chr9-134730193-G-A
• chr9-134730193-G-C
• chr9-134730193-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.925-43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 1,605,376 control chromosomes in the GnomAD database, including 162,136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13278 hom., cov: 34)
  • Exomes 𝑓: 0.45 (148858 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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=-0.97).
• BP6: Variant 9-134730193-G-A is Benign according to our data. Variant chr9-134730193-G-A is described in ClinVar as [Benign]. Clinvar id is 255101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.925-43G>A		intron_variant		ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.925-43G>A		intron_variant			NP_001265003.1
COL5A1	XM_017014266.3	c.925-43G>A		intron_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.925-43G>A		intron_variant		1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.925-43G>A		intron_variant		2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60611 AN: 151732 Hom.: 13261 Cov.: 34

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.450

GnomAD3 exomes AF: 0.478 AC: 117329 AN: 245350 Hom.: 29824 AF XY: 0.475 AC XY: 63166 AN XY: 133114

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.707

Gnomad ASJ exome AF: 0.622

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.468

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.441

Gnomad OTH exome AF: 0.487

GnomAD4 exome AF: 0.447 AC: 649937 AN: 1453526 Hom.: 148858 Cov.: 43 AF XY: 0.448 AC XY: 324079 AN XY: 723354

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.693

Gnomad4 ASJ exome AF: 0.624

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.437

Gnomad4 OTH exome AF: 0.453

GnomAD4 genome AF: 0.399 AC: 60663 AN: 151850 Hom.: 13278 Cov.: 34 AF XY: 0.407 AC XY: 30225 AN XY: 74200

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.619

Gnomad4 EAS AF: 0.480

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.453

Alfa AF: 0.439 Hom.: 2849

Bravo AF: 0.402

Asia WGS AF: 0.506 AC: 1756 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

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	-0.97
CADD	Benign	0.10
DANN	Benign	0.65

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: rs3128598; hg19: chr9-137622039; COSMIC: COSV65673422; COSMIC: COSV65673422;