rs748327110

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001848.3(COL6A1):​c.2554G>A​(p.Ala852Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,609,426 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 0.000020 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

7
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.38
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 Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17301509).
BP6
Variant 21-46003480-G-A is Benign according to our data. Variant chr21-46003480-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2141838.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000618 (9/1457218) while in subpopulation EAS AF= 0.000176 (7/39684). AF 95% confidence interval is 0.000082. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 81. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL6A1NM_001848.3 linkc.2554G>A p.Ala852Thr missense_variant 35/35 ENST00000361866.8 NP_001839.2 P12109A0A384P5H7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL6A1ENST00000361866.8 linkc.2554G>A p.Ala852Thr missense_variant 35/351 NM_001848.3 ENSP00000355180.3 P12109

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152208
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000290
AC:
7
AN:
241558
Hom.:
0
AF XY:
0.0000227
AC XY:
3
AN XY:
132324
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000396
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000618
AC:
9
AN:
1457218
Hom.:
0
Cov.:
81
AF XY:
0.00000276
AC XY:
2
AN XY:
725086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000176
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152208
Hom.:
0
Cov.:
35
AF XY:
0.0000269
AC XY:
2
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000414
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 23, 2023The c.2554G>A (p.A852T) alteration is located in exon 35 (coding exon 35) of the COL6A1 gene. This alteration results from a G to A substitution at nucleotide position 2554, causing the alanine (A) at amino acid position 852 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 03, 2020- -
Bethlem myopathy 1A Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;T
Eigen
Benign
0.073
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.76
T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Benign
0.60
N;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.74
N;.
REVEL
Uncertain
0.30
Sift
Benign
0.064
T;.
Sift4G
Uncertain
0.015
D;D
Polyphen
0.81
P;.
Vest4
0.15
MutPred
0.54
Gain of phosphorylation at A852 (P = 0.0261);.;
MVP
0.45
MPC
0.59
ClinPred
0.14
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.047
gMVP
0.52

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: rs748327110; hg19: chr21-47423394; COSMIC: COSV62614830; COSMIC: COSV62614830; API