X-31507432-C-T

Variant names:

• chrX-31507432-C-T
• rs772732788
• NM_004006.3:c.8239G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_004006.3(DMD):​c.8239G>A​(p.Ala2747Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,093,775 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2747G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 1.96
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13764742).
• BS2: High AC in GnomAdExome4 at 5 XL,AD gene. Variant has AC 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.8239G>A	p.Ala2747Thr	missense	Exon 56 of 79	NP_003997.2
	DMD	NM_004009.3		c.8227G>A	p.Ala2743Thr	missense	Exon 56 of 79	NP_004000.1
	DMD	NM_000109.4		c.8215G>A	p.Ala2739Thr	missense	Exon 56 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.8239G>A	p.Ala2747Thr	missense	Exon 56 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.8227G>A	p.Ala2743Thr	missense	Exon 56 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.4207G>A	p.Ala1403Thr	missense	Exon 28 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000290 AC: 5 AN: 172667 AF XY: 0.0000342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1093775 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 1 AN XY: 359533

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.000115 AC: 4 AN: 34835

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19308

East Asian (EAS) AF: 0.00 AC: 0 AN: 30128

South Asian (SAS) AF: 0.00 AC: 0 AN: 53512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839406

Other (OTH) AF: 0.00 AC: 0 AN: 45919

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000407 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Aug 09, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DMD c.8239G>A; p.Ala2747Thr variant (rs772732788), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 409922). This variant is found in the general population with an overall allele frequency of 0.003% (5/172667 alleles, including 2 hemizygotes) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.013). Due to limited information, the clinical significance of this variant is uncertain at this time.

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

Aug 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Duchenne muscular dystrophy Benign:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
PhyloP100		2.0
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.013
Sift	Benign	0.45	T
Sift4G	Benign	0.40	T
Polyphen		0.029	B
Vest4		0.29
MutPred		0.42		Loss of stability (P = 0.0434)
MVP		0.61
MPC		0.064
ClinPred		0.22	T
GERP RS		4.6
gMVP		0.11
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs772732788; hg19: chrX-31525549;