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GeneBe

X-32644153-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_004006.3(DMD):c.1310C>A(p.Ala437Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,094,967 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A437G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

1
2
9

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.81
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-32644153-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447251.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.36031675).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DMDNM_004006.3 linkuse as main transcriptc.1310C>A p.Ala437Asp missense_variant 11/79 ENST00000357033.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DMDENST00000357033.9 linkuse as main transcriptc.1310C>A p.Ala437Asp missense_variant 11/791 NM_004006.3 P4

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
0.00000183
AC:
2
AN:
1094967
Hom.:
0
Cov.:
29
AF XY:
0.00000277
AC XY:
1
AN XY:
360583
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:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
22
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Duchenne muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 11, 2021This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 437 of the DMD protein (p.Ala437Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DMD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In 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. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 23, 2022The p.A437D variant (also known as c.1310C>A), located in coding exon 11 of the DMD gene, results from a C to A substitution at nucleotide position 1310. The alanine at codon 437 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.42
Cadd
Uncertain
24
Dann
Uncertain
1.0
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.79
T;.;T;T;T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.36
T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.70
T
Sift4G
Benign
0.55
T;T;T;T;T
Polyphen
0.21, 0.97
.;B;.;.;D
Vest4
0.78
MutPred
0.61
.;.;Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);.;
MVP
0.55
MPC
0.12
ClinPred
0.78
D
GERP RS
5.8
gMVP
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1556875180; hg19: chrX-32662270; API