rs2645774

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000295550.9(COL6A3):c.4533G>T(p.Gly1511=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,613,952 control chromosomes in the GnomAD database, including 42,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4513 hom., cov: 32)

Exomes 𝑓: 0.23 ( 38255 hom. )

Consequence

COL6A3
ENST00000295550.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -5.14

Variant links:

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 2-237368930-C-A is Benign according to our data. Variant chr2-237368930-C-A is described in ClinVar as [Benign]. Clinvar id is 94936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237368930-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.4533G>T	p.Gly1511=	synonymous_variant	10/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.3915G>T	p.Gly1305=	synonymous_variant	9/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.2712G>T	p.Gly904=	synonymous_variant	7/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.4533G>T	p.Gly1511=	synonymous_variant	10/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.2712G>T	p.Gly904=	synonymous_variant	7/41	1		ENSP00000418285		P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.3915G>T	p.Gly1305=	synonymous_variant	9/43	5		ENSP00000315873		P12111-2
COL6A3	ENST00000684597.1 linkuse as main transcript	c.117-254G>T		intron_variant				ENSP00000508021

Frequencies

GnomAD3 genomes

AF:

0.241

AC:

36608

AN:

151946

Hom.:

4496

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.218

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.248

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.242

GnomAD3 exomes

AF:

0.238

AC:

59940

AN:

251392

Hom.:

7418

AF XY:

0.234

AC XY:

31844

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.321

Gnomad ASJ exome

AF:

0.193

Gnomad EAS exome

AF:

0.256

Gnomad SAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.196

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.216

GnomAD4 exome

AF:

0.226

AC:

330106

AN:

1461888

Hom.:

38255

Cov.:

AF XY:

0.225

AC XY:

163965

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.281

Gnomad4 AMR exome

AF:

0.319

Gnomad4 ASJ exome

AF:

0.193

Gnomad4 EAS exome

AF:

0.246

Gnomad4 SAS exome

AF:

0.242

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.221

Gnomad4 OTH exome

AF:

0.226

GnomAD4 genome

AF:

0.241

AC:

36676

AN:

152064

Hom.:

4513

Cov.:

AF XY:

0.243

AC XY:

18090

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.276

Gnomad4 AMR

AF:

0.296

Gnomad4 ASJ

AF:

0.218

Gnomad4 EAS

AF:

0.255

Gnomad4 SAS

AF:

0.255

Gnomad4 FIN

AF:

0.190

Gnomad4 NFE

AF:

0.216

Gnomad4 OTH

AF:

0.245

Alfa

AF:

0.199

Hom.:

1567

Bravo

AF:

0.251

Asia WGS

AF:

0.263

AC:

915

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2016	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 57% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 53. Only high quality variants are reported. -

Bethlem myopathy 1A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Dystonia 27

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Collagen 6-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ullrich congenital muscular dystrophy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.0

DANN

Benign

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over