rs150694150

Positions:

• chr2-237365711-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004369.4(COL6A3):​c.5825C>T​(p.Pro1942Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1942A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.00

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056588173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.5825C>T	p.Pro1942Leu	missense_variant	12/44	ENST00000295550.9
COL6A3	NM_057167.4	c.5207C>T	p.Pro1736Leu	missense_variant	11/43
COL6A3	NM_057166.5	c.4004C>T	p.Pro1335Leu	missense_variant	9/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.5825C>T	p.Pro1942Leu	missense_variant	12/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.4004C>T	p.Pro1335Leu	missense_variant	9/41	1
COL6A3	ENST00000353578.9	c.5207C>T	p.Pro1736Leu	missense_variant	11/43	5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 250324 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135404

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727208

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74354

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000977 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2023	Identified in the heterozygous state in a patient with limb-girdle muscular dystrophy in published literature and reported as a variant of uncertain significance (Nallamilli et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Benign	0.83
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.93	D;D;D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.057	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N;.;N
REVEL	Benign	0.040
Sift	Benign	0.22	T;T;T;.;T
Sift4G	Uncertain	0.025	D;T;D;D;D
Polyphen		0.93	P;B;.;.;P
Vest4		0.29
MVP		0.49
MPC		0.19
ClinPred		0.024	T
GERP RS		3.2
Varity_R		0.037
gMVP		0.40

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: rs150694150; hg19: chr2-238274354;