Variant rs1057518962 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004006.3(DMD):c.1637G>T(p.Trp546Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,594 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W546S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.37

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.1637G>T	p.Trp546Leu	missense_variant	14/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.1637G>T	p.Trp546Leu	missense_variant	14/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182410

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

66998

show subpopulations

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:

0.0000530

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097594

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

.;T;.;.;T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D

MetaSVM

Uncertain

-0.28

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-9.2

.;D;.;D;D;N

REVEL

Uncertain

0.47

Sift

Uncertain

0.0040

.;D;.;D;D;T

Sift4G

Uncertain

0.012

D;D;D;D;T;T

Polyphen

1.0, 1.0

.;D;.;.;D;.

Vest4

0.71

MutPred

0.63

.;.;Loss of MoRF binding (P = 0.029);Loss of MoRF binding (P = 0.029);.;.;

MVP

0.93

MPC

0.099

ClinPred

0.99

GERP RS

5.2

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over