rs140534207

chr21-46003561-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001848.3(COL6A1):c.2635A>G(p.Ser879Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,612,558 control chromosomes in the GnomAD database, including 4 homozygotes. 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. S879S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 35)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 3.19

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011149317).
• BP6: Variant 21-46003561-A-G is Benign according to our data. Variant chr21-46003561-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162529.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=2}. Variant chr21-46003561-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2635A>G	p.Ser879Gly	missense_variant	35/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2635A>G	p.Ser879Gly	missense_variant	35/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152194 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00182 AC: 446 AN: 245210 Hom.: 0 AF XY: 0.00181 AC XY: 243 AN XY: 133930

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000852

Gnomad FIN exome AF: 0.00887

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00125 AC: 1820 AN: 1460246 Hom.: 3 Cov.: 81 AF XY: 0.00126 AC XY: 912 AN XY: 726474

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00776

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152312 Hom.: 1 Cov.: 35 AF XY: 0.00144 AC XY: 107 AN XY: 74482

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.000661

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00187 AC: 227

EpiCase AF: 0.00136

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	COL6A1: BS1 -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2016	The S879G variant in the COL6A1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. This variant is a non-conservative amino acid substitution of a polar Serine with a non-polar Glycine at a residue that is conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. The S879G variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. We interpret S879G as a variant of unknown significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2015

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	18
Dann	Benign	0.55
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.53
Sift	Benign	0.47	T;.
Sift4G	Benign	0.39	T;T
Polyphen		1.0	D;.
Vest4		0.28
MVP		0.63
MPC		0.68
ClinPred		0.074	T
GERP RS		4.8
Varity_R		0.20
gMVP		0.81

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: rs140534207; hg19: chr21-47423475;