rs145668843

Positions:

chrX-32699247-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1BP4_ModerateBP6_Very_StrongBS2

The NM_004006.3(DMD):c.696C>G(p.Ile232Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,207,499 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 132 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00037 ( 0 hom. 128 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.51

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 -12 ACMG points.

PM1

In a region_of_interest Actin-binding (size 239) in uniprot entity DMD_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004006.3

BP4

Computational evidence support a benign effect (MetaRNN=0.24008453).

BP6

Variant X-32699247-G-C is Benign according to our data. Variant chrX-32699247-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 284717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32699247-G-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.696C>G	p.Ile232Met	missense_variant	8/79	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.696C>G	p.Ile232Met	missense_variant	8/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.000215

AC:

AN:

111607

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33839

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000287

Gnomad ASJ

AF:

0.00114

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000283

Gnomad OTH

AF:

0.000668

GnomAD3 exomes

AF:

0.000224

AC:

AN:

182849

Hom.:

AF XY:

0.000237

AC XY:

AN XY:

67575

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00174

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000295

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000374

AC:

410

AN:

1095892

Hom.:

Cov.:

AF XY:

0.000354

AC XY:

128

AN XY:

361506

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.0000853

Gnomad4 ASJ exome

AF:

0.00124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000430

Gnomad4 OTH exome

AF:

0.000457

GnomAD4 genome

AF:

0.000215

AC:

AN:

111607

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33839

show subpopulations

Gnomad4 AFR

AF:

0.0000649

Gnomad4 AMR

AF:

0.000287

Gnomad4 ASJ

AF:

0.00114

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000283

Gnomad4 OTH

AF:

0.000668

Alfa

AF:

0.000521

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2019	This variant is associated with the following publications: (PMID: 26392559) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2017	The p.Ile232Met variant (rs145668843) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.02 percent (identified on 40 out of 199,721 chromosomes, including 17 hemizygotes), and has been reported to the ClinVar database as a likely benign variant (Variation ID: 284717). The isoleucine at position 232 is moderately conserved considering 7 species (Alamut v2.10) and computational analyses of the p.Ile232Met variant on protein structure and function indicate a neutral effect (GVGD: class C0, MutationTaster: polymorphism, PolyPhen-2: benign). Overall this variant is considered to be likely benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 03, 2016

- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 21, 2017

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 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. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.0099

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

.;D;.;.;D

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.74

T;.;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Uncertain

0.54

MutationTaster

Benign

0.93

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

.;N;.;N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.0050

.;D;.;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.046, 0.0020

.;B;.;.;B

Vest4

0.64

MVP

0.94

MPC

0.021

ClinPred

0.060

GERP RS

2.8

gMVP

0.43

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