rs760815168

chr21-45998136-G-Tchr21-45998136-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001848.3(COL6A1):c.1540G>T(p.Ala514Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. A514T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19469574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.1540G>T	p.Ala514Ser	missense_variant	23/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.1540G>T	p.Ala514Ser	missense_variant	23/35	1	NM_001848.3	P1
COL6A1	ENST00000683550.1	n.315G>T		non_coding_transcript_exon_variant	4/5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460012 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.16	N;.
REVEL	Benign	0.22
Sift	Benign	0.043	D;.
Sift4G	Benign	0.15	T;T
Polyphen		0.16	B;.
Vest4		0.22
MutPred		0.30		Gain of glycosylation at A514 (P = 0.0067);Gain of glycosylation at A514 (P = 0.0067);
MVP		0.40
MPC		0.51
ClinPred		0.56	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.43

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: rs760815168; hg19: chr21-47418050;