rs128627255

chrX-32697995-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_Moderate PM2 PP5

The NM_004006.3(DMD):c.835A>G(p.Thr279Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T279M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 21)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.59

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 5 ACMG points.

• PS1: Transcript NM_004006.3 (DMD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-32697995-T-C is Pathogenic according to our data. Variant chrX-32697995-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11279.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-32697995-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.835A>G	p.Thr279Ala	missense_variant	9/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.835A>G	p.Thr279Ala	missense_variant	9/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dilated cardiomyopathy 3B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 20, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T;.;T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.88, 0.70	.;P;.;.;P
Vest4		0.58
MutPred		0.65		.;.;Gain of MoRF binding (P = 0.1496);Gain of MoRF binding (P = 0.1496);.;
MVP		0.95
MPC		0.076
ClinPred		0.75	D
GERP RS		5.6
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: rs128627255; hg19: chrX-32716112; COSMIC: COSV105167797;