rs150686304

chr21-45984390-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_001848.3(COL6A1):c.349G>A(p.Val117Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,612,754 control chromosomes in the GnomAD database, including 14 homozygotes. 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. V117A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 3.41

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-45984391-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.048485726).
• BP6: Variant 21-45984390-G-A is Benign according to our data. Variant chr21-45984390-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128813.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=6}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000558 (85/152400) while in subpopulation SAS AF= 0.00538 (26/4832). AF 95% confidence interval is 0.00377. There are 1 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.349G>A	p.Val117Met	missense_variant	3/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.349G>A	p.Val117Met	missense_variant	3/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.000571 AC: 87 AN: 152282 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00125 AC: 313 AN: 249560 Hom.: 4 AF XY: 0.00162 AC XY: 219 AN XY: 135544

Gnomad AFR exome AF: 0.000561

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.00817

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000657 AC: 960 AN: 1460354 Hom.: 13 Cov.: 33 AF XY: 0.000831 AC XY: 604 AN XY: 726486

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.00739

Gnomad4 FIN exome AF: 0.0000577

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152400 Hom.: 1 Cov.: 35 AF XY: 0.000671 AC XY: 50 AN XY: 74524

Gnomad4 AFR AF: 0.000841

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000308 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2020	This variant is associated with the following publications: (PMID: 24038877, 30467950) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	COL6A1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 25, 2014	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.77
MVP		0.88
MPC		0.22
ClinPred		0.042	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs150686304; hg19: chr21-47404304; COSMIC: COSV62611675; COSMIC: COSV62611675;