2-237324809-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004369.4(COL6A3):c.9499G>A(p.Ala3167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.552

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029504001).
• BP6: Variant 2-237324809-C-T is Benign according to our data. Variant chr2-237324809-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 848577.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.9499G>A	p.Ala3167Thr	missense_variant	44/44	ENST00000295550.9
COL6A3	NM_057167.4	c.8881G>A	p.Ala2961Thr	missense_variant	43/43
COL6A3	NM_057166.5	c.7678G>A	p.Ala2560Thr	missense_variant	41/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.9499G>A	p.Ala3167Thr	missense_variant	44/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000403 AC: 10 AN: 248104 Hom.: 0 AF XY: 0.0000596 AC XY: 8 AN XY: 134310

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000630

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461260 Hom.: 0 Cov.: 31 AF XY: 0.000169 AC XY: 123 AN XY: 726904

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000231

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 31, 2022

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	6.2
Dann	Benign	0.76
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.61	T;T;T;T;.
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.030	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.29	N;N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.15	T;T;T;.;T
Sift4G	Benign	0.37	T;T;T;T;T
Polyphen		0.0010	B;B;.;.;B
Vest4		0.070
MutPred		0.23		.;Loss of stability (P = 0.1038);.;.;.;
MVP		0.41
MPC		0.14
ClinPred		0.019	T
GERP RS		-9.9
Varity_R		0.030
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs537511128; hg19: chr2-238233452; COSMIC: COSV55090451;