chrX-32644154-C-T

Variant names:

• chrX-32644154-C-T
• rs748964279
• NM_004006.3:c.1309G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5 BP4 BS2_Supporting

The NM_004006.3(DMD):​c.1309G>A​(p.Ala437Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,095,238 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict 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. A437D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.09
• Publications: 1 publications found

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]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-32644153-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2834953).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AD geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.1309G>A	p.Ala437Thr	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.1309G>A	p.Ala437Thr	missense_variant	Exon 11 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095238 Hom.: 0 Cov.: 29 AF XY: 0.00000554 AC XY: 2 AN XY: 360832

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26298

American (AMR) AF: 0.00 AC: 0 AN: 34992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19293

East Asian (EAS) AF: 0.00 AC: 0 AN: 30153

South Asian (SAS) AF: 0.00 AC: 0 AN: 53598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40391

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840404

Other (OTH) AF: 0.00 AC: 0 AN: 45981

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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

Oct 18, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 30, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Uncertain:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 994870). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 437 of the DMD protein (p.Ala437Thr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DMD protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;.;D;D;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.94	T
PhyloP100		4.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.83	.;N;.;N;N
REVEL	Benign	0.076
Sift	Benign	0.33	.;T;.;T;T
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		0.026, 0.38	.;B;.;.;B
Vest4		0.32
MutPred		0.42		.;.;Gain of disorder (P = 0.05);Gain of disorder (P = 0.05);.;
MVP		0.61
MPC		0.10
ClinPred		0.83	D
GERP RS		5.0
gMVP		0.24
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs748964279; hg19: chrX-32662271;