X-31627740-T-C

Variant names:

• chrX-31627740-T-C
• rs886043271
• NM_004006.3:c.8150A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_004006.3(DMD):​c.8150A>G​(p.Asp2717Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,097,835 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. D2717V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 6.26
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.8150A>G	p.Asp2717Gly	missense	Exon 55 of 79	NP_003997.2
	DMD	NM_004009.3		c.8138A>G	p.Asp2713Gly	missense	Exon 55 of 79	NP_004000.1
	DMD	NM_000109.4		c.8126A>G	p.Asp2709Gly	missense	Exon 55 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.8150A>G	p.Asp2717Gly	missense	Exon 55 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.8138A>G	p.Asp2713Gly	missense	Exon 55 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.4118A>G	p.Asp1373Gly	missense	Exon 27 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097835 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 363239

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30178

South Asian (SAS) AF: 0.00 AC: 0 AN: 54090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841878

Other (OTH) AF: 0.00 AC: 0 AN: 46080

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 25, 2024

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 19, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 10, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Uncertain:1

Jul 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Duchenne muscular dystrophy Uncertain:1

Dec 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2717 of the DMD protein (p.Asp2717Gly). 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: 285966). 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 with a negative predictive value of 95%. 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

Oct 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D2717G variant (also known as c.8150A>G), located in coding exon 55 of the DMD gene, results from an A to G substitution at nucleotide position 8150. The aspartic acid at codon 2717 is replaced by glycine, an amino acid with similar properties. 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.34	T
PhyloP100		6.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.29
Sift	Benign	0.086	T
Sift4G	Benign	0.12	T
Polyphen		0.97	D
Vest4		0.50
MutPred		0.34		Gain of MoRF binding (P = 0.0651)
MVP		0.89
MPC		0.074
ClinPred		0.94	D
GERP RS		5.8
gMVP		0.50
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs886043271; hg19: chrX-31645857;