rs149882431

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_004006.3(DMD):c.2199C>T(p.Ser733Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,208,400 control chromosomes in the GnomAD database, including 1 homozygotes. There are 32 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00064 ( 1 hom., 23 hem., cov: 23)

Exomes 𝑓: 0.000057 ( 0 hom. 9 hem. )

Consequence

DMD
NM_004006.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.753

Publications

1 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant X-32518101-G-A is Benign according to our data. Variant chrX-32518101-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166856.

BP7

Synonymous conserved (PhyloP=0.753 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000645 (72/111651) while in subpopulation AFR AF = 0.00208 (64/30761). AF 95% confidence interval is 0.00167. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 72 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.2199C>T	p.Ser733Ser	synonymous_variant	Exon 18 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.2199C>T	p.Ser733Ser	synonymous_variant	Exon 18 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.000556

AC:

AN:

111598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000666

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:

0.000668

GnomAD2 exomes

AF:

0.000197

AC:

AN:

182648

AF XY:

0.0000893

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000574

AC:

AN:

1096749

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362199

show subpopulations

African (AFR)

AF:

0.00148

AC:

AN:

26379

American (AMR)

AF:

0.000313

AC:

AN:

35180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19370

East Asian (EAS)

AF:

0.00

AC:

AN:

30171

South Asian (SAS)

AF:

0.00

AC:

AN:

54051

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40516

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840908

Other (OTH)

AF:

0.000261

AC:

AN:

46044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000645

AC:

AN:

111651

Hom.:

Cov.:

AF XY:

0.000679

AC XY:

AN XY:

33855

show subpopulations

African (AFR)

AF:

0.00208

AC:

AN:

30761

American (AMR)

AF:

0.000665

AC:

AN:

10522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5983

Middle Eastern (MID)

AF:

0.00

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53097

Other (OTH)

AF:

0.000660

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

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:

0.00114

Hom.:

Bravo

AF:

0.000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP7 -

Jan 13, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 3B

Uncertain:1

Apr 28, 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;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency

Benign:1

Nov 20, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Nov 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 21, 2019

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. -

Duchenne muscular dystrophy

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.8

(source)

DANN

Benign

0.67

PhyloP100

0.75

Mutation Taster

=100/0

polymorphism

(source)

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

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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