21-45999186-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001848.3(COL6A1):c.1708G>A(p.Ala570Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000111 in 1,603,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A570E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 3.99

Publications

2 publications found

Variant links:

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

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

COL6A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031849086).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000643 (98/152390) while in subpopulation AFR AF = 0.00233 (97/41600). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.1708G>A	p.Ala570Thr	missense_variant	Exon 26 of 35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.1708G>A	p.Ala570Thr	missense_variant	Exon 26 of 35	1	NM_001848.3	ENSP00000355180.3		P12109
COL6A1	ENST00000466285.1 link	n.-214G>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000147

AC:

AN:

230968

AF XY:

0.0000802

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.0000307

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.0000551

AC:

AN:

1450656

Hom.:

Cov.:

AF XY:

0.0000458

AC XY:

AN XY:

720502

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

33380

American (AMR)

AF:

0.0000462

AC:

AN:

43244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.00

AC:

AN:

39328

South Asian (SAS)

AF:

0.00

AC:

AN:

84146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52032

Middle Eastern (MID)

AF:

0.000199

AC:

AN:

5024

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1107686

Other (OTH)

AF:

0.000117

AC:

AN:

59928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000643

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41600

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000240

Hom.:

Bravo

AF:

0.000722

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00251

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000182

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Mar 23, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

Nov 30, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously as heterozygous in an individual with clinically suspected limb-girdle muscular dystrophy; however, the authors classified A570T as a variant of uncertain significance and additional clinical information was not provided (PMID: 30564623); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32906206, 30564623, 37273706) -

Bethlem myopathy 1A

Benign:1

Aug 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.032

T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.7

L;.

PhyloP100

4.0

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;.

REVEL

Uncertain

0.58

Sift

Benign

0.068

T;.

Sift4G

Benign

0.24

T;T

Polyphen

1.0

D;.

Vest4

0.55

MVP

0.78

MPC

0.82

ClinPred

0.030

GERP RS

4.5

Varity_R

0.092

gMVP

0.42

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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