rs3109675

Variant names:

• chr9-134731709-T-C
• rs3109675
• NM_000093.5:c.1332+46T>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: -3.67
• Publications: 5 publications found

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]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1332+46T>C		intron_variant	Intron 8 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1332+46T>C		intron_variant	Intron 8 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.1332+46T>C		intron_variant	Intron 8 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1332+46T>C		intron_variant	Intron 8 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1332+46T>C		intron_variant	Intron 8 of 65	2		ENSP00000360885.4
COL5A1	ENST00000469093.1	n.71+46T>C		intron_variant	Intron 1 of 1	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

GnomAD2 exomes AF: 0.510 AC: 107002 AN: 209666 AF XY: 0.505

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 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

African (AFR) AF: 0.212 AC: 6965 AN: 32814

American (AMR) AF: 0.706 AC: 30302 AN: 42910

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 15870 AN: 23982

East Asian (EAS) AF: 0.472 AC: 18522 AN: 39252

South Asian (SAS) AF: 0.476 AC: 38333 AN: 80524

European-Finnish (FIN) AF: 0.495 AC: 22331 AN: 45126

Middle Eastern (MID) AF: 0.510 AC: 2828 AN: 5544

European-Non Finnish (NFE) AF: 0.479 AC: 522866 AN: 1091406

Other (OTH) AF: 0.483 AC: 28369 AN: 58718

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

African (AFR) AF: 0.227 AC: 9434 AN: 41518

American (AMR) AF: 0.586 AC: 8973 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2281 AN: 3472

East Asian (EAS) AF: 0.482 AC: 2482 AN: 5154

South Asian (SAS) AF: 0.469 AC: 2261 AN: 4826

European-Finnish (FIN) AF: 0.494 AC: 5229 AN: 10592

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.476 AC: 32334 AN: 67960

Other (OTH) AF: 0.472 AC: 997 AN: 2114

Alfa AF: 0.460 Hom.: 3253

Bravo AF: 0.423

Asia WGS AF: 0.510 AC: 1766 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibromuscular dysplasia, multifocal Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type Benign:1

Jul 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.023
DANN	Benign	0.15
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3109675; hg19: chr9-137623555;