X-32441296-G-A

Position:

chrX-32441296-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004006.3(DMD):c.3805C>T(p.His1269Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000274 in 1,205,019 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1269P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 3 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.69

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20494142).

BP6

Variant X-32441296-G-A is Benign according to our data. Variant chrX-32441296-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228586.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.3805C>T	p.His1269Tyr	missense_variant	28/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.3805C>T	p.His1269Tyr	missense_variant	28/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

111307

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33667

show subpopulations

Gnomad AFR

AF:

0.000455

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000383

AC:

AN:

182584

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67362

show subpopulations

Gnomad AFR exome

AF:

0.000459

Gnomad AMR exome

AF:

0.0000366

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:

0.00

GnomAD4 exome

AF:

0.0000174

AC:

AN:

1093712

Hom.:

Cov.:

AF XY:

0.00000833

AC XY:

AN XY:

359978

show subpopulations

Gnomad4 AFR exome

AF:

0.000533

Gnomad4 AMR exome

AF:

0.0000569

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:

0.00000239

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.000126

AC:

AN:

111307

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33667

show subpopulations

Gnomad4 AFR

AF:

0.000455

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 19, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2015

The p.His1269Tyr variant in DMD has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/8368 African chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs15 1150099). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. Computational splicing tools suggest this variant may lead to the creation of a novel 5' splice site; however, this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of the p.His1269Tyr variant is uncertain. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The p.H1269Y variant (also known as c.3805C>T), located in coding exon 28 of the DMD gene, results from a C to T substitution at nucleotide position 3805. The histidine at codon 1269 is replaced by tyrosine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.0049% (10/204406) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was 0.0474% (9/19003) of African alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

.;T;.;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.53

D;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.12

.;N;.;N

REVEL

Benign

0.090

Sift

Benign

1.0

.;T;.;T

Sift4G

Benign

0.64

T;T;T;T

Polyphen

0.38

.;B;.;.

Vest4

0.34

MVP

0.49

MPC

0.065

ClinPred

0.047

GERP RS

4.1

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over