X-32645016-C-T

Position:

• chrX-32645016-C-T

Variant summary

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

The NM_004006.3(DMD):​c.1097G>A​(p.Gly366Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000519 in 1,098,133 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 9 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.02

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21585327).
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.1097G>A	p.Gly366Glu	missense_variant	10/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.1097G>A	p.Gly366Glu	missense_variant	10/79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183381 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67839

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000519 AC: 57 AN: 1098133 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 9 AN XY: 363533

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: 0.0000677

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -

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

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 10, 2018

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 24, 2021

- -

Duchenne muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 13, 2021

This sequence change replaces glycine with glutamic acid at codon 366 of the DMD protein (p.Gly366Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs763144501, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of DMD-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 499974). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.20	.;T;.;.;T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.85	T;.;T;T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.33	.;N;.;N;N
REVEL	Benign	0.067
Sift	Benign	1.0	.;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.14, 0.81	.;B;.;.;P
Vest4		0.30
MutPred		0.49		.;.;Gain of disorder (P = 0.0518);Gain of disorder (P = 0.0518);.;
MVP		0.61
MPC		0.10
ClinPred		0.24	T
GERP RS		4.7
gMVP		0.21

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: rs763144501; hg19: chrX-32663133;