rs773102625

Positions:

• chrX-31774052-C-A
• chrX-31774052-C-G
• chrX-31774052-C-T

Variant summary

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

The NM_004006.3(DMD):​c.7450G>T​(p.Asp2484Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 109,989 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.52

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.7450G>T	p.Asp2484Tyr	missense_variant	51/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.7450G>T	p.Asp2484Tyr	missense_variant	51/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.00000909 AC: 1 AN: 109989 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32227

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000909 AC: 1 AN: 109989 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32227

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T;T;.;.;T;.;.;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;.;.;.;D;.;D;D;.
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;.;D;.;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D;D;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 1.0, 0.98	.;D;D;D;.;D;.;.;D
Vest4		0.58, 0.59, 0.62, 0.63, 0.64, 0.64, 0.63
MutPred		0.46		.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0731);.;
MVP		0.76
MPC		0.12
ClinPred		0.98	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs773102625; hg19: chrX-31792169;