rs368996545

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6BS2_Supporting

The NM_004006.3(DMD):c.10846A>G(p.Thr3616Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,209,007 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. 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. T3616P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 7 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 4.12

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:

ENSG00000297249 (HGNC:):

ENSG00000297249 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14121437).

BP6

Variant X-31146366-T-C is Benign according to our data. Variant chrX-31146366-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286925.

BS2

High AC in GnomAd4 at 7 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.10846A>G	p.Thr3616Ala	missense_variant	Exon 76 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.10846A>G	p.Thr3616Ala	missense_variant	Exon 76 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

AF:

0.0000624

AC:

AN:

112237

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183156

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000155

AC:

AN:

1096770

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

362330

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26366

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30169

South Asian (SAS)

AF:

0.0000555

AC:

AN:

54089

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3821

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

841208

Other (OTH)

AF:

0.0000217

AC:

AN:

46018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

0.0000624

AC:

AN:

112237

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34411

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30871

American (AMR)

AF:

0.00

AC:

AN:

10641

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3578

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53232

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Aug 20, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 26, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DMD p.Thr3616Ala variant (rs368996545) has not been reported in the medical literature, nor has it been previously identified in our laboratory. The p.Thr3616Ala variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.0039% (identified in 7 out of 178,443 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 286925). The threonine at codon 3616 is highly conserved considering 7 species up to chicken (Alamut software v2.10.0), but computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Thr3616Ala variant cannot be determined with certainty. -

Cardiovascular phenotype

Uncertain:1

Jul 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T3616A variant (also known as c.10846A>G), located in coding exon 76 of the DMD gene, results from an A to G substitution at nucleotide position 10846. The threonine at codon 3616 is replaced by alanine, an amino acid with similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.0027% (5/183156) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0076% (1/13151) of African alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Benign:1

Feb 07, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Duchenne muscular dystrophy

Benign:1

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

.;.;T;T;T;.;.;T;.;.;.;T;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.56

T;T;.;.;.;.;T;.;T;T;T;.;T;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.14

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

PhyloP100

4.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.72

N;N;.;N;N;N;.;N;.;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.69

T;T;.;T;T;T;.;T;.;T;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0070, 0.36, 0.013, 0.59

.;.;.;B;B;B;.;P;.;.;.;B;B;.

Vest4

0.19

MVP

0.83

MPC

0.034

ClinPred

0.058

GERP RS

5.4

gMVP

0.51

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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