Genetic Variant NM_004369.4:c.3446G>A (chr2-237374645-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004369.4(COL6A3):c.3446G>A(p.Arg1149Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 1,614,144 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1149W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 4 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.674

Publications

3 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042245984).

BP6

Variant 2-237374645-C-T is Benign according to our data. Variant chr2-237374645-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198793.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (336/152282) while in subpopulation AFR AF = 0.00741 (308/41564). AF 95% confidence interval is 0.00673. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR,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.3446G>A	p.Arg1149Gln	missense	Exon 8 of 44	NP_004360.2	D9ZGF2
COL6A3	NM_057167.4		c.2828G>A	p.Arg943Gln	missense	Exon 7 of 43	NP_476508.2	P12111-2
COL6A3	NM_057166.5		c.1625G>A	p.Arg542Gln	missense	Exon 5 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.3446G>A	p.Arg1149Gln	missense	Exon 8 of 44	ENSP00000295550.4	P12111-1
COL6A3	ENST00000472056.5	TSL:1	c.1625G>A	p.Arg542Gln	missense	Exon 5 of 41	ENSP00000418285.1	P12111-4
COL6A3	ENST00000392004.7	TSL:1	c.2828G>A	p.Arg943Gln	missense	Exon 7 of 8	ENSP00000375861.3	P12111-5

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

333

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00734

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000581

AC:

146

AN:

251238

AF XY:

0.000449

show subpopulations

Gnomad AFR exome

AF:

0.00819

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000275

AC:

402

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00911

AC:

305

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1112010

Other (OTH)

AF:

0.000580

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00221

AC:

336

AN:

152282

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00741

AC:

308

AN:

41564

American (AMR)

AF:

0.00111

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68026

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000658

Hom.:

Bravo

AF:

0.00243

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000741

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bethlem myopathy 1A (1)

COL6A3-related disorder (1)

Collagen 6-related myopathy (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.17

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.042

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.3

PhyloP100

0.67

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.93

REVEL

Benign

0.19

Sift

Benign

0.19

Sift4G

Benign

0.21

Polyphen

0.76

Vest4

0.058

MVP

0.80

MPC

0.25

ClinPred

0.0042

GERP RS

2.2

Varity_R

0.11

gMVP

0.69

Mutation Taster

=94/6

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over