rs111228504

Positions:

• chr2-237361735-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):​c.6156+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,656 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (124 hom.)
• Consequence: COL6A3 NM_004369.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006520
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.73

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 2-237361735-G-A is Benign according to our data. Variant chr2-237361735-G-A is described in ClinVar as [Benign]. Clinvar id is 94952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237361735-G-A is described in Lovd as [Benign]. Variant chr2-237361735-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.009 (1370/152248) while in subpopulation NFE AF= 0.0134 (909/68026). AF 95% confidence interval is 0.0126. There are 7 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6156+4C>T		splice_region_variant, intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5538+4C>T		splice_region_variant, intron_variant			NP_476508.2
COL6A3	NM_057166.5	c.4335+4C>T		splice_region_variant, intron_variant			NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6156+4C>T		splice_region_variant, intron_variant		1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4335+4C>T		splice_region_variant, intron_variant		1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5538+4C>T		splice_region_variant, intron_variant		5		ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.00902 AC: 1372 AN: 152132 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0114 AC: 2875 AN: 251462 Hom.: 25 AF XY: 0.0121 AC XY: 1638 AN XY: 135910

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00951

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0120

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0117 AC: 17064 AN: 1461408 Hom.: 124 Cov.: 31 AF XY: 0.0118 AC XY: 8567 AN XY: 727054

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00946

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.00693

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.00900 AC: 1370 AN: 152248 Hom.: 7 Cov.: 32 AF XY: 0.00817 AC XY: 608 AN XY: 74442

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00997

Gnomad4 FIN AF: 0.00613

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0131 Hom.: 3

Bravo AF: 0.00925

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0169

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	COL6A3: BP4, BS1, BS2 -

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
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.015
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.098
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: rs111228504; hg19: chr2-238270378;