rs151242451

Positions:

• chrX-32518039-C-A
• chrX-32518039-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.2261G>T​(p.Gly754Val) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,208,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G754C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 40 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.07

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010589749).
• BP6: Variant X-32518039-C-A is Benign according to our data. Variant chrX-32518039-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 194844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32518039-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000924 (103/111509) while in subpopulation AFR AF= 0.00293 (90/30723). AF 95% confidence interval is 0.00244. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.2261G>T	p.Gly754Val	missense_variant	18/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.2261G>T	p.Gly754Val	missense_variant	18/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.000924 AC: 103 AN: 111455 Hom.: 0 Cov.: 23 AF XY: 0.000772 AC XY: 26 AN XY: 33671

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000954

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: 0.00

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000295 AC: 54 AN: 183220 Hom.: 0 AF XY: 0.000221 AC XY: 15 AN XY: 67724

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.000219

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: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000113 AC: 124 AN: 1097071 Hom.: 0 Cov.: 29 AF XY: 0.000110 AC XY: 40 AN XY: 362495

Gnomad4 AFR exome AF: 0.00387

Gnomad4 AMR exome AF: 0.000284

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: 0.00000238

Gnomad4 OTH exome AF: 0.000217

GnomAD4 genome AF: 0.000924 AC: 103 AN: 111509 Hom.: 0 Cov.: 23 AF XY: 0.000771 AC XY: 26 AN XY: 33735

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.000952

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00299 Hom.: 0

Bravo AF: 0.00110

ESP6500AA AF: 0.00235 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 01, 2016	p.Gly754Val in exon 18 of DMD: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (32/8397) of African chromosome s, including 8 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs151242451). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2018	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 12, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

DMD-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Uncertain	-0.056	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.077	T;T;T;T;D
Polyphen		1.0, 0.80	.;D;.;.;P
Vest4		0.77
MVP		0.80
MPC		0.13
ClinPred		0.027	T
GERP RS		5.1
gMVP		0.33

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: rs151242451; hg19: chrX-32536156;