2-237324168-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004369.4(COL6A3):c.*606A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,662 control chromosomes in the GnomAD database, including 1,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1006 hom., cov: 32)
  • Exomes 𝑓: 0.071 (2 hom.)
• Consequence: COL6A3 NM_004369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.132

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-237324168-T-A is Benign according to our data. Variant chr2-237324168-T-A is described in ClinVar as [Benign]. Clinvar id is 335091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.*606A>T		3_prime_UTR_variant	44/44	ENST00000295550.9
COL6A3	NM_057166.5	c.*606A>T		3_prime_UTR_variant	41/41
COL6A3	NM_057167.4	c.*606A>T		3_prime_UTR_variant	43/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.*606A>T		3_prime_UTR_variant	44/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16005 AN: 151960 Hom.: 1000 Cov.: 32

Gnomad AFR AF: 0.0884

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0797

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0927

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.0714 AC: 42 AN: 588 Hom.: 2 Cov.: 0 AF XY: 0.0610 AC XY: 20 AN XY: 328

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0892

Gnomad4 NFE exome AF: 0.0303

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.105 AC: 16032 AN: 152074 Hom.: 1006 Cov.: 32 AF XY: 0.107 AC XY: 7985 AN XY: 74346

Gnomad4 AFR AF: 0.0885

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.0797

Gnomad4 NFE AF: 0.0927

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0988 Hom.: 105

Bravo AF: 0.108

Asia WGS AF: 0.236 AC: 818 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.79
Cadd	Benign	10
Dann	Benign	0.77

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: rs7436; hg19: chr2-238232811; COSMIC: COSV55087597; COSMIC: COSV55087597;