rs1556853254

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000357033.9(DMD):​c.1399A>T​(p.Thr467Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T467T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Consequence

DMD
ENST00000357033.9 missense

Scores

1
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.66
Variant links:
Genes affected
DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DMDNM_004006.3 linkuse as main transcriptc.1399A>T p.Thr467Ser missense_variant 12/79 ENST00000357033.9 NP_003997.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkuse as main transcriptc.1399A>T p.Thr467Ser missense_variant 12/791 NM_004006.3 ENSP00000354923 P4

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Duchenne muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2017In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DMD-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 467 of the DMD protein (p.Thr467Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.56
BayesDel_addAF
Benign
0.0068
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
.;T;.;.;T
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
T;.;T;T;D
M_CAP
Benign
0.078
D
MetaRNN
Uncertain
0.57
D;D;D;D;D
MetaSVM
Benign
-0.40
T
MutationTaster
Benign
0.96
D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-2.8
.;D;.;D;D
REVEL
Uncertain
0.29
Sift
Uncertain
0.0080
.;D;.;D;D
Sift4G
Uncertain
0.011
D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;.;D
Vest4
0.57
MutPred
0.35
.;.;Gain of MoRF binding (P = 0.1145);Gain of MoRF binding (P = 0.1145);.;
MVP
0.82
MPC
0.086
ClinPred
0.97
D
GERP RS
5.6
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: rs1556853254; hg19: chrX-32632503; API