NM_001848.3:c.1684A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001848.3(COL6A1):​c.1684A>G​(p.Ile562Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,600,954 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: š‘“ 0.000072 ( 0 hom., cov: 33)
Exomes š‘“: 0.00012 ( 1 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: -0.235
Variant links:
Genes affected
COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.071637064).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00012 (174/1448714) while in subpopulation NFE AF= 0.000151 (167/1106698). AF 95% confidence interval is 0.000132. There are 1 homozygotes in gnomad4_exome. There are 76 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A1NM_001848.3 linkc.1684A>G p.Ile562Val missense_variant Exon 26 of 35 ENST00000361866.8 NP_001839.2 P12109A0A384P5H7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A1ENST00000361866.8 linkc.1684A>G p.Ile562Val missense_variant Exon 26 of 35 1 NM_001848.3 ENSP00000355180.3 P12109
COL6A1ENST00000466285.1 linkn.-238A>G upstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152240
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000175
AC:
4
AN:
228854
Hom.:
0
AF XY:
0.0000162
AC XY:
2
AN XY:
123456
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000389
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000120
AC:
174
AN:
1448714
Hom.:
1
Cov.:
34
AF XY:
0.000106
AC XY:
76
AN XY:
719276
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.000151
Gnomad4 OTH exome
AF:
0.000117
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152240
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000966
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Apr 01, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 03, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 05, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2 -

Bethlem myopathy 1A Uncertain:1Benign:1
Jan 05, 2018
Centogene AG - the Rare Disease Company
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 13, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Nov 03, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1684A>G (p.I562V) alteration is located in exon 26 (coding exon 26) of the COL6A1 gene. This alteration results from a A to G substitution at nucleotide position 1684, causing the isoleucine (I) at amino acid position 562 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
0.13
DANN
Benign
0.49
DEOGEN2
Benign
0.17
T;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.30
T;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.072
T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
0.0
N;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
0.15
N;.
REVEL
Uncertain
0.31
Sift
Benign
0.74
T;.
Sift4G
Benign
0.51
T;T
Polyphen
0.0
B;.
Vest4
0.19
MVP
0.49
MPC
0.20
ClinPred
0.020
T
GERP RS
-9.0
Varity_R
0.017
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs374315921; hg19: chr21-47419076; API