rs905571950

Positions:

• chrX-32346011-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004006.3(DMD):​c.5518G>C​(p.Asp1840His) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,207,628 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1840E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000019 (0 hom. 4 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.16

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.5518G>C	p.Asp1840His	missense_variant	39/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.5518G>C	p.Asp1840His	missense_variant	39/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111270 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33516

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 21 AN: 1096358 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 362306

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000250

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111270 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33516

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 31, 2016

- -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 21, 2018

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2021

This sequence change replaces aspartic acid with histidine at codon 1840 of the DMD protein (p.Asp1840His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 447258). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;.;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;.;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	.;D;.;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	.;D;.;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.60
MutPred		0.24		.;.;Loss of ubiquitination at K1843 (P = 0.0156);Loss of ubiquitination at K1843 (P = 0.0156);.;
MVP		0.78
MPC		0.11
ClinPred		0.96	D
GERP RS		5.8
gMVP		0.34

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: rs905571950; hg19: chrX-32364128;