rs117470181

Variant names:

• chr21-45986722-A-G
• rs117470181
• NM_001848.3:c.588+37A>G

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.588+37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,538,340 control chromosomes in the GnomAD database, including 1,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (94 hom., cov: 33)
  • Exomes 𝑓: 0.013 (1061 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.370
• Publications: 3 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=-0.88).
• BP6: Variant 21-45986722-A-G is Benign according to our data. Variant chr21-45986722-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.588+37A>G		intron_variant	Intron 4 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.588+37A>G		intron_variant	Intron 4 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1672 AN: 151434 Hom.: 94 Cov.: 33

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00693

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.0825

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00817

GnomAD2 exomes AF: 0.0276 AC: 4063 AN: 147114 AF XY: 0.0310

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00570

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0128 AC: 17721 AN: 1386788 Hom.: 1061 Cov.: 35 AF XY: 0.0148 AC XY: 10108 AN XY: 684298

African (AFR) AF: 0.000826 AC: 26 AN: 31486

American (AMR) AF: 0.0132 AC: 471 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.00633 AC: 159 AN: 25136

East Asian (EAS) AF: 0.188 AC: 6726 AN: 35712

South Asian (SAS) AF: 0.0816 AC: 6446 AN: 79036

European-Finnish (FIN) AF: 0.00352 AC: 140 AN: 39728

Middle Eastern (MID) AF: 0.0142 AC: 66 AN: 4660

European-Non Finnish (NFE) AF: 0.00260 AC: 2803 AN: 1077640

Other (OTH) AF: 0.0153 AC: 884 AN: 57746

GnomAD4 genome AF: 0.0110 AC: 1674 AN: 151552 Hom.: 94 Cov.: 33 AF XY: 0.0133 AC XY: 985 AN XY: 74044

African (AFR) AF: 0.00109 AC: 45 AN: 41158

American (AMR) AF: 0.0140 AC: 214 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00693 AC: 24 AN: 3464

East Asian (EAS) AF: 0.143 AC: 723 AN: 5068

South Asian (SAS) AF: 0.0832 AC: 399 AN: 4794

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 67906

Other (OTH) AF: 0.00760 AC: 16 AN: 2104

Alfa AF: 0.00578 Hom.: 4

Bravo AF: 0.0108

Asia WGS AF: 0.0850 AC: 295 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 16, 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: Likely 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	-0.88
CADD	Benign	0.91
DANN	Benign	0.37
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117470181; hg19: chr21-47406636;