rs367735348

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_004006.3(DMD):c.8234T>C(p.Ile2745Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,205,471 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.32

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 Likely_benign. Variant got -5 ACMG points.

BP6

Variant X-31507437-A-G is Benign according to our data. Variant chrX-31507437-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526102.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.8234T>C	p.Ile2745Thr	missense_variant	56/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.8234T>C	p.Ile2745Thr	missense_variant	56/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112254

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34406

show subpopulations

Gnomad AFR

AF:

0.0000971

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:

0.0000175

AC:

AN:

171011

Hom.:

AF XY:

0.0000350

AC XY:

AN XY:

57077

show subpopulations

Gnomad AFR exome

AF:

0.0000799

Gnomad AMR exome

AF:

0.0000755

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:

0.0000128

AC:

AN:

1093217

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

359033

show subpopulations

Gnomad4 AFR exome

AF:

0.0000759

Gnomad4 AMR exome

AF:

0.0000575

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:

0.00000953

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112254

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34406

show subpopulations

Gnomad4 AFR

AF:

0.0000971

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:

0.0000699

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jun 12, 2018

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2022

The p.I2745T variant (also known as c.8234T>C), located in coding exon 56 of the DMD gene, results from a T to C substitution at nucleotide position 8234. The isoleucine at codon 2745 is replaced by threonine, an amino acid with similar properties. Based on data from gnomAD, the C allele has an overall frequency of 0.0018% (3/171011) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was 0.0080% (1/12509) of African alleles. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

-0.020

Cadd

Uncertain

Dann

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

T;.;.;.;.;T;.;T;T;.

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.41

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.1

D;.;D;D;D;.;D;.;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

D;.;D;D;D;.;D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0, 0.0

.;.;D;D;D;.;B;.;.;D

Vest4

0.75, 0.75, 0.77, 0.74, 0.85, 0.72, 0.87, 0.74, 0.75

MVP

0.89

MPC

0.029

ClinPred

0.43

GERP RS

4.3

gMVP

0.63

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