rs116655315

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_004369.4(COL6A3):​c.9116C>T​(p.Thr3039Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000805 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

1
6
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 7.57
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.061486244).
BP6
Variant 2-237334739-G-A is Benign according to our data. Variant chr2-237334739-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288613.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL6A3NM_004369.4 linkuse as main transcriptc.9116C>T p.Thr3039Met missense_variant 41/44 ENST00000295550.9 NP_004360.2 P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3NM_057167.4 linkuse as main transcriptc.8498C>T p.Thr2833Met missense_variant 40/43 NP_476508.2 P12111-2Q8N4Z1Q63HQ4
COL6A3NM_057166.5 linkuse as main transcriptc.7295C>T p.Thr2432Met missense_variant 38/41 NP_476507.3 P12111-4B7ZW00

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkuse as main transcriptc.9116C>T p.Thr3039Met missense_variant 41/441 NM_004369.4 ENSP00000295550.4 P12111-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000183
AC:
46
AN:
251474
Hom.:
0
AF XY:
0.000132
AC XY:
18
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.00208
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.0000821
AC:
120
AN:
1461860
Hom.:
0
Cov.:
60
AF XY:
0.0000729
AC XY:
53
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000447
Gnomad4 ASJ exome
AF:
0.00237
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152248
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000694
Hom.:
0
Bravo
AF:
0.000128
ExAC
AF:
0.000181
AC:
22
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 24, 2024In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 12, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 11, 2017- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 09, 2024The c.9116C>T (p.T3039M) alteration is located in exon 41 (coding exon 40) of the COL6A3 gene. This alteration results from a C to T substitution at nucleotide position 9116, causing the threonine (T) at amino acid position 3039 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Dystonia 27;C5935581:Bethlem myopathy 1C;C5935583:Ullrich congenital muscular dystrophy 1C Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 04, 2024- -
Bethlem myopathy 1A Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023- -
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
23
DANN
Benign
0.60
DEOGEN2
Benign
0.23
.;T;.;T;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D;D;D;D;.
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.061
T;T;T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.2
.;M;.;.;.
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-2.1
N;N;N;.;N
REVEL
Benign
0.24
Sift
Uncertain
0.0010
D;D;D;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.99
D;D;.;.;D
Vest4
0.44
MVP
0.66
MPC
0.15
ClinPred
0.15
T
GERP RS
4.9
Varity_R
0.080
gMVP
0.36

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.

Other links and lift over

dbSNP: rs116655315; hg19: chr2-238243382; API