rs540554122

Variant names:

• chr21-46003563-C-A
• rs540554122
• NM_001848.3:c.2637C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46003563-C-A
• chr21-46003563-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001848.3(COL6A1):​c.2637C>A​(p.Ser879Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S879G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.915

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.2637C>A	p.Ser879Arg	missense_variant	Exon 35 of 35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.2637C>A	p.Ser879Arg	missense_variant	Exon 35 of 35	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245032 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000913

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 35

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	3.3
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.76		Loss of glycosylation at S879 (P = 0.0071);.;
MVP		0.90
MPC		0.85
ClinPred		0.96	D
GERP RS		-0.60
Varity_R		0.45
gMVP		0.92

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: rs540554122; hg19: chr21-47423477;