dbSNP rs73998894: COL6A3:p.Arg1395Trp (chr2-237371834-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004369.4(COL6A3):c.4183C>T(p.Arg1395Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,448 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1395Q) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0055 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 8 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.400

Publications

6 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AR, SD, AD 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
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=0.008807689).

BP6

Variant 2-237371834-G-A is Benign according to our data. Variant chr2-237371834-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (834/152034) while in subpopulation AFR AF = 0.0193 (799/41466). AF 95% confidence interval is 0.0182. There are 7 homozygotes in GnomAd4. There are 387 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL6A3	NM_004369.4	MANE Select	c.4183C>T	p.Arg1395Trp	missense	Exon 9 of 44	NP_004360.2	D9ZGF2
COL6A3	NM_057167.4		c.3565C>T	p.Arg1189Trp	missense	Exon 8 of 43	NP_476508.2	P12111-2
COL6A3	NM_057166.5		c.2362C>T	p.Arg788Trp	missense	Exon 6 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.4183C>T	p.Arg1395Trp	missense	Exon 9 of 44	ENSP00000295550.4	P12111-1
COL6A3	ENST00000472056.5	TSL:1	c.2362C>T	p.Arg788Trp	missense	Exon 6 of 41	ENSP00000418285.1	P12111-4
COL6A3	ENST00000392004.7	TSL:1	c.3565C>T	p.Arg1189Trp	missense	Exon 8 of 8	ENSP00000375861.3	P12111-5

Frequencies

GnomAD3 genomes

AF:

0.00548

AC:

832

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00135

AC:

338

AN:

251014

AF XY:

0.000796

show subpopulations

Gnomad AFR exome

AF:

0.0188

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000553

AC:

808

AN:

1461414

Hom.:

Cov.:

AF XY:

0.000486

AC XY:

353

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.0200

AC:

668

AN:

33480

American (AMR)

AF:

0.000626

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000567

AC:

AN:

52946

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1112006

Other (OTH)

AF:

0.000944

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00549

AC:

834

AN:

152034

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

387

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.0193

AC:

799

AN:

41466

American (AMR)

AF:

0.00150

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67980

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00209

Hom.:

Bravo

AF:

0.00603

ESP6500AA

AF:

0.0193

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00172

AC:

209

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Bethlem myopathy 1A (1)

COL6A3-related disorder (1)

not specified (1)

Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.074

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.4

PhyloP100

0.40

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.53

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.59

MVP

0.92

MPC

0.66

ClinPred

0.035

GERP RS

-0.36

PromoterAI

-0.091

Neutral

(source)

Varity_R

0.54

gMVP

0.57

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over