rs1131296

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.9206C>T(p.Thr3069Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,612,638 control chromosomes in the GnomAD database, including 121,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10885 hom., cov: 32)

Exomes 𝑓: 0.39 ( 110584 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.655

Publications

34 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=7.188022E-4).

BP6

Variant 2-237334649-G-A is Benign according to our data. Variant chr2-237334649-G-A is described in ClinVar as Benign. ClinVar VariationId is 95018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.9206C>T	p.Thr3069Ile	missense_variant	Exon 41 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.8588C>T	p.Thr2863Ile	missense_variant	Exon 40 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.7385C>T	p.Thr2462Ile	missense_variant	Exon 38 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.9206C>T	p.Thr3069Ile	missense_variant	Exon 41 of 44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56226

AN:

151894

Hom.:

10891

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.523

Gnomad AMR

AF:

0.351

Gnomad ASJ

AF:

0.397

Gnomad EAS

AF:

0.478

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.504

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.389

GnomAD2 exomes

AF:

0.385

AC:

96600

AN:

250848

AF XY:

0.388

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.311

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.476

Gnomad FIN exome

AF:

0.493

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.409

GnomAD4 exome

AF:

0.386

AC:

564375

AN:

1460626

Hom.:

110584

Cov.:

AF XY:

0.386

AC XY:

280206

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.278

AC:

9294

AN:

33452

American (AMR)

AF:

0.316

AC:

14125

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

10342

AN:

26128

East Asian (EAS)

AF:

0.505

AC:

20048

AN:

39698

South Asian (SAS)

AF:

0.328

AC:

28298

AN:

86200

European-Finnish (FIN)

AF:

0.487

AC:

25982

AN:

53404

Middle Eastern (MID)

AF:

0.429

AC:

2266

AN:

5282

European-Non Finnish (NFE)

AF:

0.388

AC:

430785

AN:

1111466

Other (OTH)

AF:

0.385

AC:

23235

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

18273

36546

54818

73091

91364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13250

26500

39750

53000

66250

<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:

0.370

AC:

56228

AN:

152012

Hom.:

10885

Cov.:

AF XY:

0.375

AC XY:

27871

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.282

AC:

11695

AN:

41464

American (AMR)

AF:

0.351

AC:

5361

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

1380

AN:

3472

East Asian (EAS)

AF:

0.479

AC:

2474

AN:

5170

South Asian (SAS)

AF:

0.328

AC:

1574

AN:

4798

European-Finnish (FIN)

AF:

0.504

AC:

5307

AN:

10538

Middle Eastern (MID)

AF:

0.456

AC:

134

AN:

294

European-Non Finnish (NFE)

AF:

0.397

AC:

27007

AN:

67966

Other (OTH)

AF:

0.388

AC:

819

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1820

3640

5460

7280

9100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.390

Hom.:

40093

Bravo

AF:

0.355

TwinsUK

AF:

0.391

AC:

1449

ALSPAC

AF:

0.385

AC:

1484

ESP6500AA

AF:

0.285

AC:

1256

ESP6500EA

AF:

0.402

AC:

3456

ExAC

AF:

0.388

AC:

47094

Asia WGS

AF:

0.385

AC:

1337

AN:

3478

EpiCase

AF:

0.398

EpiControl

AF:

0.402

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 14, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 45% 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: 42. Only high quality variants are reported. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 09, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dystonia 27

Benign:1

Jul 30, 2021

Genome-Nilou Lab

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. -

Ullrich congenital muscular dystrophy 1A

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.9

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.17

.;T;.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.56

T;T;T;T;.

MetaRNN

Benign

0.00072

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

.;N;.;.;.

PhyloP100

0.66

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.3

N;N;N;.;N

REVEL

Benign

0.034

Sift

Benign

0.26

T;T;T;.;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.0030

B;B;.;.;B

Vest4

0.052

MPC

0.16

ClinPred

0.0070

GERP RS

-1.1

Varity_R

0.042

gMVP

0.52

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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