rs11690358

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004369.4(COL6A3):c.8962A>G(p.Met2988Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0953 in 1,613,478 control chromosomes in the GnomAD database, including 8,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.072 ( 491 hom., cov: 33)

Exomes 𝑓: 0.098 ( 7705 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.05

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

Bethlem myopathy 1A
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1C
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
dystonia 27
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013721287).

BP6

Variant 2-237336138-T-C is Benign according to our data. Variant chr2-237336138-T-C is described in ClinVar as Benign. ClinVar VariationId is 95013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL6A3	NM_004369.4 link	c.8962A>G	p.Met2988Val	missense_variant	Exon 40 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 link	c.8344A>G	p.Met2782Val	missense_variant	Exon 39 of 43		NP_476508.2
COL6A3	NM_057166.5 link	c.7141A>G	p.Met2381Val	missense_variant	Exon 37 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.8962A>G	p.Met2988Val	missense_variant	Exon 40 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes

AF:

0.0723

AC:

10999

AN:

152178

Hom.:

490

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0312

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.0498

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00943

Gnomad SAS

AF:

0.0637

Gnomad FIN

AF:

0.0911

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0692

GnomAD2 exomes

AF:

0.0758

AC:

18824

AN:

248494

AF XY:

0.0780

show subpopulations

Gnomad AFR exome

AF:

0.0292

Gnomad AMR exome

AF:

0.0402

Gnomad ASJ exome

AF:

0.107

Gnomad EAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.0943

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.0752

GnomAD4 exome

AF:

0.0977

AC:

142820

AN:

1461182

Hom.:

7705

Cov.:

AF XY:

0.0967

AC XY:

70320

AN XY:

726876

show subpopulations

African (AFR)

AF:

0.0278

AC:

930

AN:

33476

American (AMR)

AF:

0.0424

AC:

1898

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

2905

AN:

26130

East Asian (EAS)

AF:

0.00967

AC:

384

AN:

39700

South Asian (SAS)

AF:

0.0651

AC:

5619

AN:

86250

European-Finnish (FIN)

AF:

0.0932

AC:

4923

AN:

52820

Middle Eastern (MID)

AF:

0.0493

AC:

284

AN:

5764

European-Non Finnish (NFE)

AF:

0.108

AC:

120419

AN:

1111938

Other (OTH)

AF:

0.0904

AC:

5458

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

7311

14623

21934

29246

36557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4370

8740

13110

17480

21850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0722

AC:

11001

AN:

152296

Hom.:

491

Cov.:

AF XY:

0.0705

AC XY:

5253

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0313

AC:

1303

AN:

41574

American (AMR)

AF:

0.0497

AC:

761

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

365

AN:

3466

East Asian (EAS)

AF:

0.00946

AC:

AN:

5182

South Asian (SAS)

AF:

0.0635

AC:

306

AN:

4818

European-Finnish (FIN)

AF:

0.0911

AC:

967

AN:

10612

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6966

AN:

68014

Other (OTH)

AF:

0.0681

AC:

144

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

535

1069

1604

2138

2673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0905

Hom.:

1511

Bravo

AF:

0.0686

TwinsUK

AF:

0.116

AC:

431

ALSPAC

AF:

0.108

AC:

418

ESP6500AA

AF:

0.0244

AC:

100

ESP6500EA

AF:

0.0908

AC:

749

ExAC

AF:

0.0753

AC:

9074

Asia WGS

AF:

0.0480

AC:

166

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.100

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Feb 02, 2016

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 07, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Sep 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.039

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.13

.;T;.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.12

T;T;T;T;.

MetaRNN

Benign

0.0014

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-1.0

.;N;.;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.25

PROVEAN

Benign

0.0

N;N;N;.;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T;.;T

Sift4G

Benign

0.61

T;T;T;T;T

Polyphen

0.0

B;B;.;.;B

Vest4

0.013

MPC

0.15

ClinPred

0.000010

GERP RS

-4.8

Varity_R

0.057

gMVP

0.078

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over