X-32501818-T-C

Position:

• chrX-32501818-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000357033.9(DMD):​c.2317A>G​(p.Lys773Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K773T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DMD ENST00000357033.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.39

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant X-32501818-T-C is Pathogenic according to our data. Variant chrX-32501818-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11251.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.2317A>G	p.Lys773Glu	missense_variant	19/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.2317A>G	p.Lys773Glu	missense_variant	19/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	0.98	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.3	.;N;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.050	.;D;.;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.74
MutPred		0.58		.;.;Loss of MoRF binding (P = 0.0021);Loss of MoRF binding (P = 0.0021);
MVP		0.94
MPC		0.092
ClinPred		0.90	D
GERP RS		5.3
gMVP		0.39

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: rs128626244; hg19: chrX-32519935; COSMIC: COSV63771096;