rs370459675

Positions:

• chrX-32545201-T-A
• chrX-32545201-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004006.3(DMD):​c.2126A>T​(p.Gln709Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.2126A>T	p.Gln709Leu	missense_variant	17/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.2126A>T	p.Gln709Leu	missense_variant	17/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 11, 2020

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2017

In summary, this variant has uncertain impact on DMD function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a DMD-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with leucine at codon 709 of the DMD protein (p.Gln709Leu). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T;.;.;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;D;D;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	.;N;.;N;D
REVEL	Benign	0.29
Sift	Benign	0.048	.;D;.;D;D
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.42, 0.80	.;B;.;.;P
Vest4		0.34
MutPred		0.28		.;.;Gain of catalytic residue at Q709 (P = 0.0415);Gain of catalytic residue at Q709 (P = 0.0415);.;
MVP		0.72
MPC		0.041
ClinPred		0.83	D
GERP RS		5.6
gMVP		0.24

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: rs370459675; hg19: chrX-32563318;