rs886044628

Positions:

• chrX-31146333-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004006.3(DMD):​c.10879A>G​(p.Met3627Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,096,924 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. 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. M3627K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.27

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18075418).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.10879A>G	p.Met3627Val	missense_variant	76/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.10879A>G	p.Met3627Val	missense_variant	76/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096924 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 3 AN XY: 362466

Gnomad4 AFR exome AF: 0.0000379

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2022	- -

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 08, 2019

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2022

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3627 of the DMD protein (p.Met3627Val). This variant is not present in population databases (gnomAD 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: 291040). 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 tolerated. 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	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.24	.;.;T;T;T;.;.;T;.;.;.;T;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;.;.;.;.;D;.;D;D;D;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.70	D;D;D;D;D;D;D;D;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.67	N;N;.;N;N;N;.;N;.;N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.34	T;T;.;T;T;T;.;D;.;D;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.017, 0.0010, 0.073	.;.;.;B;B;B;.;B;.;.;.;B;B;.
Vest4		0.25
MutPred		0.17		.;.;.;.;.;.;.;.;.;Loss of loop (P = 0.1242);.;.;.;.;
MVP		0.73
MPC		0.017
ClinPred		0.63	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs886044628; hg19: chrX-31164450; COSMIC: COSV100629006;