rs760439

Variant names:

• chr21-45992610-G-A
• rs760439
• NM_001848.3:c.1273-138G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45992610-G-A
• chr21-45992610-G-C
• chr21-45992610-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.1273-138G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,057,048 control chromosomes in the GnomAD database, including 11,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1985 hom., cov: 34)
  • Exomes 𝑓: 0.14 (9367 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.02
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-45992610-G-A is Benign according to our data. Variant chr21-45992610-G-A is described in ClinVar as Benign. ClinVar VariationId is 681671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1273-138G>A		intron_variant	Intron 18 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1273-138G>A		intron_variant	Intron 18 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23622 AN: 152140 Hom.: 1979 Cov.: 34

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0934

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.139 AC: 125904 AN: 904790 Hom.: 9367 AF XY: 0.140 AC XY: 64166 AN XY: 458260

African (AFR) AF: 0.230 AC: 4887 AN: 21288

American (AMR) AF: 0.0726 AC: 2167 AN: 29850

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 2960 AN: 19006

East Asian (EAS) AF: 0.0650 AC: 2162 AN: 33272

South Asian (SAS) AF: 0.156 AC: 9640 AN: 61814

European-Finnish (FIN) AF: 0.117 AC: 5353 AN: 45902

Middle Eastern (MID) AF: 0.142 AC: 451 AN: 3172

European-Non Finnish (NFE) AF: 0.142 AC: 92435 AN: 649440

Other (OTH) AF: 0.142 AC: 5849 AN: 41046

GnomAD4 genome AF: 0.155 AC: 23659 AN: 152258 Hom.: 1985 Cov.: 34 AF XY: 0.154 AC XY: 11452 AN XY: 74450

African (AFR) AF: 0.226 AC: 9409 AN: 41552

American (AMR) AF: 0.0932 AC: 1426 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3472

East Asian (EAS) AF: 0.0722 AC: 374 AN: 5182

South Asian (SAS) AF: 0.152 AC: 735 AN: 4822

European-Finnish (FIN) AF: 0.112 AC: 1188 AN: 10618

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9554 AN: 67998

Other (OTH) AF: 0.139 AC: 294 AN: 2114

Alfa AF: 0.145 Hom.: 206

Bravo AF: 0.154

Asia WGS AF: 0.118 AC: 410 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.48
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760439; hg19: chr21-47412524;