rs199588981

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_004006.3(DMD):c.2291A>G(p.Asn764Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000196 in 1,209,195 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 87 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. N764K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 11 hem., cov: 22)

Exomes 𝑓: 0.00020 ( 0 hom. 76 hem. )

Consequence

DMD
NM_004006.3 missense, splice_region

Scores

Splicing: ADA: 0.9979

Clinical Significance

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

Conservation

PhyloP100: 4.11

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 -8 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant X-32518009-T-C is Benign according to our data. Variant chrX-32518009-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288446.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chrX-32518009-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000206 (23/111913) while in subpopulation EAS AF= 0.00451 (16/3549). AF 95% confidence interval is 0.00283. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.2291A>G	p.Asn764Ser	missense_variant, splice_region_variant	18/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.2291A>G	p.Asn764Ser	missense_variant, splice_region_variant	18/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

111860

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

34020

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000949

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00449

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000371

AC:

AN:

183211

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

67717

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00375

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000195

AC:

214

AN:

1097282

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

AN XY:

362712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00282

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.000197

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.000260

GnomAD4 genome

AF:

0.000206

AC:

AN:

111913

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

34083

show subpopulations

Gnomad4 AFR

AF:

0.0000648

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00451

Gnomad4 SAS

AF:

0.000377

Gnomad4 FIN

AF:

0.000165

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000266

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000338

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	DMD: PP3, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jan 23, 2017

- -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 02, 2019

- -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

Cadd

Pathogenic

Dann

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.;D;D;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.0091

T;T;T;T;T

MetaSVM

Benign

-0.83

MutationTaster

Benign

0.97

N;N;N

PrimateAI

Uncertain

0.64

Sift4G

Uncertain

0.032

D;D;D;D;T

Polyphen

0.22, 0.39

.;B;.;.;B

Vest4

0.30

MVP

0.79

MPC

0.084

ClinPred

0.021

GERP RS

3.9

gMVP

0.086

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.97

Position offset: 5

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