rs200596739

Positions:

Variant summary

Our verdict is Likely benign. Variant got -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).

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:6

Conservation

PhyloP100: 6.09

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 Likely_benign. Variant got -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 id is 201760.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=2}. Variant chrX-32463545-T-A is described in Lovd as [Benign]. Variant chrX-32463545-T-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.3326A>T	p.Asn1109Ile	missense_variant	25/79	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.3326A>T	p.Asn1109Ile	missense_variant	25/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

112033

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

AN XY:

34207

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

GnomAD3 exomes

AF:

0.000210

AC:

AN:

161551

Hom.:

AF XY:

0.000160

AC XY:

AN XY:

50139

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 SAS exome

AF:

0.0000610

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

Gnomad4 AFR exome

AF:

0.0000381

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000470

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000191

Gnomad4 FIN exome

AF:

0.00130

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.000175

GnomAD4 genome

AF:

0.000402

AC:

AN:

112033

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

AN XY:

34207

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000377

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00246

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000366

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	DMD: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 04, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	- -

Dilated cardiomyopathy 3B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 10, 2018

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. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

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

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

MutationTaster

Benign

1.0

D;D

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

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

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