rs148781346

Positions:

chrX-32411892-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.4093C>T(p.Leu1365Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,208,913 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 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).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., 12 hem., cov: 23)

Exomes 𝑓: 0.000072 ( 0 hom. 23 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 8.09

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06169322).

BP6

Variant X-32411892-G-A is Benign according to our data. Variant chrX-32411892-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94611.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000629 (70/111273) while in subpopulation AFR AF= 0.00215 (66/30665). AF 95% confidence interval is 0.00173. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.4093C>T	p.Leu1365Phe	missense_variant	30/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.4093C>T	p.Leu1365Phe	missense_variant	30/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.000629

AC:

AN:

111222

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

AN XY:

33430

show subpopulations

Gnomad AFR

AF:

0.00216

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000289

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:

0.000670

GnomAD3 exomes

AF:

0.000181

AC:

AN:

182632

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

67352

show subpopulations

Gnomad AFR exome

AF:

0.00213

Gnomad AMR exome

AF:

0.000146

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:

0.000222

GnomAD4 exome

AF:

0.0000720

AC:

AN:

1097640

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

363134

show subpopulations

Gnomad4 AFR exome

AF:

0.00258

Gnomad4 AMR exome

AF:

0.000142

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:

0.00

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.000629

AC:

AN:

111273

Hom.:

Cov.:

AF XY:

0.000358

AC XY:

AN XY:

33491

show subpopulations

Gnomad4 AFR

AF:

0.00215

Gnomad4 AMR

AF:

0.000289

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:

0.000662

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000899

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Leu1365Phe va riant in DMD has not been previously reported in individuals with muscular dystr ophy, but has been identified in 0.19% (35/18082) of African chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs 148781346). This variant has been reported in ClinVar (Variation ID: 94611). Ple ase note that for diseases with clinical variability, reduced penetrance, or rec essive inheritance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analysis su ggest that the p.Leu1365Phe variant may impact the protein, though this informat ion is not predictive enough to determine pathogenicity. In summary, while the c linical significance of the p.Leu1365Phe variant is uncertain, its frequency sug gests that it is more likely to be benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2023	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2021

- -

DMD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2020

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). -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

This alteration is classified as likely 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

Uncertain

0.41

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

.;D;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;.;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.062

T;T;T;T

MetaSVM

Uncertain

0.20

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

.;D;.;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

.;D;.;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.52

MVP

0.88

MPC

0.11

ClinPred

0.086

GERP RS

5.7

gMVP

0.39

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