rs3791000

Positions:

chr2-237371715-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000392004.7(COL6A3):c.3684G>A(p.Ser1228=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,573,014 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 138 hom. )

Consequence

COL6A3
ENST00000392004.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.792

Variant links:

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]

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 2-237371715-C-T is Benign according to our data. Variant chr2-237371715-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237371715-C-T is described in Lovd as [Benign]. Variant chr2-237371715-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.792 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00524 (797/152236) while in subpopulation EAS AF= 0.0427 (221/5178). AF 95% confidence interval is 0.0381. There are 20 homozygotes in gnomad4. There are 552 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4 linkuse as main transcript	c.4285+17G>A		intron_variant		ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.4285+17G>A		intron_variant		1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.00525

AC:

799

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0430

Gnomad SAS

AF:

0.0320

Gnomad FIN

AF:

0.0338

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.0102

AC:

2287

AN:

225194

Hom.:

AF XY:

0.0111

AC XY:

1354

AN XY:

121438

show subpopulations

Gnomad AFR exome

AF:

0.000318

Gnomad AMR exome

AF:

0.000168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0390

Gnomad SAS exome

AF:

0.0331

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.00739

GnomAD4 exome

AF:

0.00457

AC:

6486

AN:

1420778

Hom.:

138

Cov.:

AF XY:

0.00528

AC XY:

3707

AN XY:

702140

show subpopulations

Gnomad4 AFR exome

AF:

0.000251

Gnomad4 AMR exome

AF:

0.000154

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0387

Gnomad4 SAS exome

AF:

0.0306

Gnomad4 FIN exome

AF:

0.0264

Gnomad4 NFE exome

AF:

0.000619

Gnomad4 OTH exome

AF:

0.00732

GnomAD4 genome

AF:

0.00524

AC:

797

AN:

152236

Hom.:

Cov.:

AF XY:

0.00742

AC XY:

552

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0427

Gnomad4 SAS

AF:

0.0320

Gnomad4 FIN

AF:

0.0338

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00139

Hom.:

Bravo

AF:

0.00227

Asia WGS

AF:

0.0510

AC:

175

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 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. -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 21, 2021

- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.17

DANN

Benign

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over