rs3790993

Positions:

Variant summary

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

The NM_004369.4(COL6A3):c.6855G>C(p.Gly2285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,458 control chromosomes in the GnomAD database, including 235,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2285G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.56 ( 23792 hom., cov: 31)

Exomes 𝑓: 0.54 ( 211272 hom. )

Consequence

COL6A3
NM_004369.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.233

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=-0.82).

BP6

Variant 2-237350171-C-G is Benign according to our data. Variant chr2-237350171-C-G is described in ClinVar as [Benign]. Clinvar id is 94968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237350171-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.233 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.6855G>C	p.Gly2285=	synonymous_variant	28/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.6237G>C	p.Gly2079=	synonymous_variant	27/43
COL6A3	NM_057166.5 linkuse as main transcript	c.5034G>C	p.Gly1678=	synonymous_variant	25/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.6855G>C	p.Gly2285=	synonymous_variant	28/44	1	NM_004369.4	P1	P12111-1
COL6A3	ENST00000472056.5 linkuse as main transcript	c.5034G>C	p.Gly1678=	synonymous_variant	25/41	1			P12111-4
COL6A3	ENST00000353578.9 linkuse as main transcript	c.6237G>C	p.Gly2079=	synonymous_variant	27/43	5			P12111-2
COL6A3	ENST00000491769.1 linkuse as main transcript	n.1109G>C		non_coding_transcript_exon_variant	5/20	5

Frequencies

GnomAD3 genomes

AF:

0.556

AC:

84468

AN:

151800

Hom.:

23760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.586

Gnomad AMI

AF:

0.645

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.581

Gnomad EAS

AF:

0.664

Gnomad SAS

AF:

0.514

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.537

Gnomad OTH

AF:

0.556

GnomAD3 exomes

AF:

0.542

AC:

136333

AN:

251332

Hom.:

37415

AF XY:

0.543

AC XY:

73756

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.460

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.654

Gnomad SAS exome

AF:

0.513

Gnomad FIN exome

AF:

0.586

Gnomad NFE exome

AF:

0.540

Gnomad OTH exome

AF:

0.560

GnomAD4 exome

AF:

0.536

AC:

783904

AN:

1461540

Hom.:

211272

Cov.:

AF XY:

0.536

AC XY:

389581

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.584

Gnomad4 AMR exome

AF:

0.466

Gnomad4 ASJ exome

AF:

0.572

Gnomad4 EAS exome

AF:

0.672

Gnomad4 SAS exome

AF:

0.515

Gnomad4 FIN exome

AF:

0.583

Gnomad4 NFE exome

AF:

0.530

Gnomad4 OTH exome

AF:

0.556

GnomAD4 genome

AF:

0.557

AC:

84557

AN:

151918

Hom.:

23792

Cov.:

AF XY:

0.556

AC XY:

41296

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.586

Gnomad4 AMR

AF:

0.503

Gnomad4 ASJ

AF:

0.581

Gnomad4 EAS

AF:

0.664

Gnomad4 SAS

AF:

0.515

Gnomad4 FIN

AF:

0.594

Gnomad4 NFE

AF:

0.537

Gnomad4 OTH

AF:

0.561

Alfa

AF:

0.515

Hom.:

5735

Bravo

AF:

0.552

Asia WGS

AF:

0.601

AC:

2091

AN:

3478

EpiCase

AF:

0.542

EpiControl

AF:

0.544

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Jan 25, 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, 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 71% 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: 66. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2018	- -

Bethlem myopathy 1A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 23, 2017

- -

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 12, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.0

DANN

Benign

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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