rs876657777

Positions:

• chrX-32644215-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004006.3(DMD):​c.1248A>T​(p.Glu416Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 0.717

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31078762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.1248A>T	p.Glu416Asp	missense_variant	11/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.1248A>T	p.Glu416Asp	missense_variant	11/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2016

The p.Glu416Asp variant in DMD has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of the p.Glu416Asp vari ant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;T;.;.;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.72	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	.;N;.;N;D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	.;D;.;D;T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	.;D;.;.;D
Vest4		0.41
MutPred		0.43		.;.;Loss of methylation at K411 (P = 0.1073);Loss of methylation at K411 (P = 0.1073);.;
MVP		0.72
MPC		0.075
ClinPred		0.96	D
GERP RS		4.6
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs876657777; hg19: chrX-32662332;