rs3109675

Positions:

• chr9-134731709-T-C
• chr9-134731709-T-G

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.1332+46T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.477 in 1,572,416 control chromosomes in the GnomAD database, including 183,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14956 hom., cov: 34)
  • Exomes 𝑓: 0.48 (168622 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.67

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=-1.04).
• BP6: Variant 9-134731709-T-C is Benign according to our data. Variant chr9-134731709-T-C is described in ClinVar as [Benign]. Clinvar id is 255049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.1332+46T>C		intron_variant		ENST00000371817.8
COL5A1	NM_001278074.1	c.1332+46T>C		intron_variant
COL5A1	XM_017014266.3	c.1332+46T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.1332+46T>C		intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.1332+46T>C		intron_variant		2		A2
COL5A1	ENST00000469093.1	n.71+46T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64395 AN: 152022 Hom.: 14943 Cov.: 34

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.468

GnomAD3 exomes AF: 0.510 AC: 107002 AN: 209666 Hom.: 28583 AF XY: 0.505 AC XY: 57767 AN XY: 114480

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.722

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.471

Gnomad SAS exome AF: 0.483

Gnomad FIN exome AF: 0.501

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.483 AC: 686386 AN: 1420276 Hom.: 168622 Cov.: 33 AF XY: 0.484 AC XY: 339569 AN XY: 702306

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.706

Gnomad4 ASJ exome AF: 0.662

Gnomad4 EAS exome AF: 0.472

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.495

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.424 AC: 64442 AN: 152140 Hom.: 14956 Cov.: 34 AF XY: 0.431 AC XY: 32031 AN XY: 74378

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.482

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.472

Alfa AF: 0.466 Hom.: 3234

Bravo AF: 0.423

Asia WGS AF: 0.510 AC: 1766 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

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. -

Ehlers-Danlos syndrome, classic type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 03, 2018

- -

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	-1.0
CADD	Benign	0.023
DANN	Benign	0.15

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: rs3109675; hg19: chr9-137623555;