rs1800269

chrX-32448508-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):c.3734C>T(p.Thr1245Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,206,985 control chromosomes in the GnomAD database, including 169 homozygotes. There are 4,240 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. T1245T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0099 (14 hom., 315 hem., cov: 23)
  • Exomes 𝑓: 0.012 (155 hom. 3925 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 6.09

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=0.0023860931).
• BP6: Variant X-32448508-G-A is Benign according to our data. Variant chrX-32448508-G-A is described in ClinVar as [Benign]. Clinvar id is 94604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32448508-G-A is described in Lovd as [Benign]. Variant chrX-32448508-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.3734C>T	p.Thr1245Ile	missense_variant	27/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.3734C>T	p.Thr1245Ile	missense_variant	27/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1105 AN: 111014 Hom.: 14 Cov.: 23 AF XY: 0.00937 AC XY: 315 AN XY: 33632

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00872

Gnomad AMR AF: 0.0401

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.000285

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.00295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0149

GnomAD3 exomes AF: 0.0189 AC: 3452 AN: 182401 Hom.: 112 AF XY: 0.0144 AC XY: 971 AN XY: 67275

Gnomad AFR exome AF: 0.00199

Gnomad AMR exome AF: 0.0894

Gnomad ASJ exome AF: 0.00820

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.00438

Gnomad NFE exome AF: 0.00919

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0118 AC: 12882 AN: 1095919 Hom.: 155 Cov.: 30 AF XY: 0.0108 AC XY: 3925 AN XY: 362543

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.00877

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.00370

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00953

GnomAD4 genome AF: 0.00995 AC: 1105 AN: 111066 Hom.: 14 Cov.: 23 AF XY: 0.00935 AC XY: 315 AN XY: 33694

Gnomad4 AFR AF: 0.00211

Gnomad4 AMR AF: 0.0400

Gnomad4 ASJ AF: 0.0103

Gnomad4 EAS AF: 0.000286

Gnomad4 SAS AF: 0.00184

Gnomad4 FIN AF: 0.00295

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00978 Hom.: 410

Bravo AF: 0.0143

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0135 AC: 39

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.0109 AC: 73

ExAC AF: 0.0139 AC: 1686

EpiCase AF: 0.0104

EpiControl AF: 0.00845

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Thr1245Ile in exon 27 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 1.1% (73/6728) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs1800269). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2020	Variant summary: DMD c.3734C>T (p.Thr1245Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.019 in 182401 control chromosomes, predominantly at a frequency of 0.089 within the Latino subpopulation in the gnomAD database, including 112 homozygotes and 971 hemizygotes. The observed variant frequency within Latino control individuals in the gnomAD database is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies phenotype, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2017

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

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. -

Duchenne muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;.;D;D
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.89	P;P
PrimateAI	Uncertain	0.51	T
Sift4G	Uncertain	0.049	D;D;D;D
Polyphen		0.83	.;P;.;.
Vest4		0.31
MPC		0.019
ClinPred		0.036	T
GERP RS		3.1
gMVP		0.15

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: rs1800269; hg19: chrX-32466625; COSMIC: COSV63803746;