rs144358858

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

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). Synonymous variant affecting the same amino acid position (i.e. A570A) has been classified as Likely benign.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.1708G>A	p.Ala570Thr	missense_variant	26/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.1708G>A	p.Ala570Thr	missense_variant	26/35	1	NM_001848.3	P1

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

GnomAD3 exomes

AF:

0.000147

AC:

AN:

230968

Hom.:

AF XY:

0.0000802

AC XY:

AN XY:

124720

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 SAS 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

Gnomad4 AFR exome

AF:

0.00198

Gnomad4 AMR exome

AF:

0.0000462

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000643

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.00233

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000191

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2023	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Reported 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 (Nallamilli et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32906206, 30564623) -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2023

- -

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

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;.

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over