chrX-32809539-G-T

Position:

• chrX-32809539-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004006.3(DMD):​c.603C>A​(p.Asn201Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34

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 3 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 239) in uniprot entity DMD_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004006.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30432266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.603C>A	p.Asn201Lys	missense_variant	7/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.603C>A	p.Asn201Lys	missense_variant	7/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183337 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67797

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.;.;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Uncertain	0.27	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	.;N;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.070	.;T;.;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.78, 0.95	.;P;.;.;P
Vest4		0.43
MutPred		0.52		.;.;Gain of methylation at N201 (P = 0.0141);Gain of methylation at N201 (P = 0.0141);.;
MVP		0.90
MPC		0.091
ClinPred		0.51	D
GERP RS		4.3
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs750180929; hg19: chrX-32827656; COSMIC: COSV55869322;