X-32644153-G-C

Variant names:

• chrX-32644153-G-C
• rs1556875180
• NM_004006.3:c.1310C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004006.3(DMD):​c.1310C>G​(p.Ala437Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.81

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-32644153-G-C is Pathogenic according to our data. Variant chrX-32644153-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32644153-G-C is described in Lovd as [Pathogenic]. Variant chrX-32644153-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.1310C>G	p.Ala437Gly	missense_variant	Exon 11 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.1310C>G	p.Ala437Gly	missense_variant	Exon 11 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Sep 03, 2019

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant has been confirmed to occur de novo in one individual with clinical features associated with this gene. -

Duchenne muscular dystrophy Pathogenic:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 437 of the DMD protein (p.Ala437Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Duchenne or Becker muscular dystrophy (PMID: 16770791, 19937601, 32559196; internal data). ClinVar contains an entry for this variant (Variation ID: 447251). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;T;.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Benign	-0.60	T
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	.;N;.;N;N
REVEL	Benign	0.27
Sift	Benign	0.21	.;T;.;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.81, 0.97	.;P;.;.;D
Vest4		0.58
MutPred		0.71		.;.;Gain of disorder (P = 0.0596);Gain of disorder (P = 0.0596);.;
MVP		0.77
MPC		0.095
ClinPred		0.89	D
GERP RS		5.8
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 5
DS_DL_spliceai		0.52		Position offset: -21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556875180; hg19: chrX-32662270;