X-31479069-A-T

Variant names:

• chrX-31479069-A-T
• NM_004006.3:c.8582T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004006.3(DMD):​c.8582T>A​(p.Val2861Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.8582T>A	p.Val2861Glu	missense_variant	Exon 58 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.8582T>A	p.Val2861Glu	missense_variant	Exon 58 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.8582T>A (p.Val2861Glu) results in a non-conservative amino acid change located in repeat 23 of the central rod domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 182800 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8582T>A in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;T;T;.;.;T;.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;.;.;.;T;.;T;T;.
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.73	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	N;.;N;N;D;.;D;.;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.017	D;.;D;D;D;.;D;.;D;D
Sift4G	Benign	0.076	T;T;T;T;T;D;D;D;D;T
Polyphen		0.90, 1.0, 0.96, 1.0, 0.97	.;.;P;D;D;.;D;.;.;D
Vest4		0.76, 0.71, 0.72, 0.70, 0.68, 0.67, 0.69, 0.69, 0.70
MutPred		0.48		.;.;.;.;.;.;.;.;Gain of disorder (P = 0.0054);.;
MVP		0.91
MPC		0.059
ClinPred		0.94	D
GERP RS		5.1
gMVP		0.60

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-31497186;