rs200596739

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_004006.3(DMD):c.3326A>T(p.Asn1109Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,198,708 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 80 hemizygotes in GnomAD. 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. N1109S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.00017 ( 0 hom. 61 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 6.09

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
dilated cardiomyopathy 3B
Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
Duchenne and Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Duchenne muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
progressive muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-32463545-T-A is Benign according to our data. Variant chrX-32463545-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 201760.

BS2

High AC in GnomAd4 at 45 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.3326A>T	p.Asn1109Ile	missense_variant	Exon 25 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.3326A>T	p.Asn1109Ile	missense_variant	Exon 25 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

112033

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00246

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000210

AC:

AN:

161551

AF XY:

0.000160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000281

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00110

Gnomad NFE exome

AF:

0.000216

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000166

AC:

180

AN:

1086675

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

AN XY:

354223

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26240

American (AMR)

AF:

0.00

AC:

AN:

34175

Ashkenazi Jewish (ASJ)

AF:

0.000470

AC:

AN:

19151

East Asian (EAS)

AF:

0.00

AC:

AN:

29836

South Asian (SAS)

AF:

0.0000191

AC:

AN:

52272

European-Finnish (FIN)

AF:

0.00130

AC:

AN:

39853

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.000130

AC:

109

AN:

835382

Other (OTH)

AF:

0.000175

AC:

AN:

45653

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000402

AC:

AN:

112033

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

AN XY:

34207

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30760

American (AMR)

AF:

0.00

AC:

AN:

10543

Ashkenazi Jewish (ASJ)

AF:

0.000377

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2721

European-Finnish (FIN)

AF:

0.00246

AC:

AN:

6093

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

53274

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000366

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Sep 07, 2023

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 04, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DMD c.3326A>T; p.Asn1109Ile variant (rs200596739), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 201760). This variant is found in the general population with an overall allele frequency of 0.02% (48/183570 alleles, including 11 hemizygotes) in the Genome Aggregation Database. The asparagine at codon 1109 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Asn1109Ile variant is uncertain at this time. -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DMD: BS2 -

Feb 19, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asn1109Ile variant in DMD is classified as benign because it has been iden tified in 0.13% (23/17581) of Finnish chromosomes and 12 homozygotes by gnomAD ( http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

May 23, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 3B

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Duchenne muscular dystrophy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain

0.35

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

.;T;.;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;.;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Benign

-0.36

PhyloP100

6.1

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.9

.;D;.;D

REVEL

Uncertain

0.47

Sift

Benign

0.052

.;T;.;T

Sift4G

Benign

0.064

T;T;T;T

Polyphen

1.0

.;D;.;.

Vest4

0.78

MutPred

0.60

.;.;Loss of disorder (P = 0.0436);Loss of disorder (P = 0.0436);

MVP

0.79

MPC

0.13

ClinPred

0.31

GERP RS

5.4

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over