rs1556875180

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-32644153-G-A
• chrX-32644153-G-C
• chrX-32644153-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_004006.3(DMD):​c.1310C>T​(p.Ala437Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,094,968 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 0 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 4 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 447251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.1310C>T	p.Ala437Val	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>T	p.Ala437Val	missense_variant	Exon 11 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1094968 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 360584

African (AFR) AF: 0.00 AC: 0 AN: 26285

American (AMR) AF: 0.00 AC: 0 AN: 34996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19289

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 53629

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40375

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 840138

Other (OTH) AF: 0.00 AC: 0 AN: 45974

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duchenne muscular dystrophy Uncertain:1

May 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the DMD protein (p.Ala437Val). 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. ClinVar contains an entry for this variant (Variation ID: 1427855). 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. This variant disrupts the p.Ala437 amino acid residue in DMD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16770791, 19937601, 32559196; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	0.14
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	.;T;.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.80	T
PhyloP100		6.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	.;N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.14	.;T;.;T;T
Sift4G	Benign	0.063	T;T;T;T;D
Polyphen		0.81, 0.95	.;P;.;.;P
Vest4		0.62
MutPred		0.46		.;.;Loss of ubiquitination at K441 (P = 0.0877);Loss of ubiquitination at K441 (P = 0.0877);.;
MVP		0.62
MPC		0.10
ClinPred		0.92	D
GERP RS		5.8
gMVP		0.33
Mutation Taster		=37/63	disease causing

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: rs1556875180; hg19: chrX-32662270;