rs773941387

Positions:

• chrX-31478185-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004006.3(DMD):​c.8858C>A​(p.Ala2953Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000911 in 1,097,437 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000091 (0 hom. 4 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.8858C>A	p.Ala2953Asp	missense_variant	59/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.8858C>A	p.Ala2953Asp	missense_variant	59/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181600 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000367

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097437 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 362833

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

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: 0.00000951

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2018

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2022

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2953 of the DMD protein (p.Ala2953Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 571602). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 submitter

clinical testing

Ambry Genetics

Aug 31, 2022

The p.A2953D variant (also known as c.8858C>A), located in coding exon 59 of the DMD gene, results from a C to A substitution at nucleotide position 8858. The alanine at codon 2953 is replaced by aspartic acid, an amino acid with dissimilar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.0006% (1/181600) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0037% (1/27262) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T;D;T;.;.;T;.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;.;.;.;D;.;D;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D;.;D;D;D;.;D;.;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;.;D;D;D;.;D;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;D;D;D;.;D;.;.;D
Vest4		0.95, 0.93, 0.95, 0.94, 0.93, 0.94, 0.92, 0.91, 0.94
MutPred		0.67		.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0302);.;
MVP		0.93
MPC		0.092
ClinPred		0.92	D
GERP RS		5.4
gMVP		0.87

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

Other links and lift over

dbSNP: rs773941387; hg19: chrX-31496302;