chrX-32573812-C-A

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

8
6
2

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]

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
DMDNM_004006.3 linkuse as main transcriptc.1637G>T p.Trp546Leu missense_variant 14/79 ENST00000357033.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DMDENST00000357033.9 linkuse as main transcriptc.1637G>T p.Trp546Leu missense_variant 14/791 NM_004006.3 P4

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.00000548
AC:
1
AN:
182410
Hom.:
0
AF XY:
0.0000149
AC XY:
1
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:
1
AN:
1097594
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
1
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.:
23

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
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
.;T;.;.;T;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;D;D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D
MetaSVM
Uncertain
-0.28
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.80
T
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
D
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.

Other links and lift over

dbSNP: rs1057518962; hg19: chrX-32591929; API