rs773656507

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.7747A>G(p.Thr2583Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,210,553 control chromosomes in the GnomAD database, including 1 homozygotes. There are 36 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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. T2583I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000069 ( 1 hom. 36 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.34

Publications

0 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060219526).

BP6

Variant X-31679500-T-C is Benign according to our data. Variant chrX-31679500-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197951.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000692 (76/1098054) while in subpopulation SAS AF = 0.00137 (74/54142). AF 95% confidence interval is 0.00112. There are 1 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 76 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.7747A>G	p.Thr2583Ala	missense_variant	Exon 53 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.7747A>G	p.Thr2583Ala	missense_variant	Exon 53 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112445

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000728

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000764

AC:

AN:

183239

AF XY:

0.0000886

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000692

AC:

AN:

1098054

Hom.:

Cov.:

AF XY:

0.0000991

AC XY:

AN XY:

363418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26401

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30204

South Asian (SAS)

AF:

0.00137

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841991

Other (OTH)

AF:

0.0000434

AC:

AN:

46092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112499

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34633

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31021

American (AMR)

AF:

0.00

AC:

AN:

10641

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3570

South Asian (SAS)

AF:

0.000730

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6145

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53296

Other (OTH)

AF:

0.00

AC:

AN:

1529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jun 19, 2018

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Duchenne muscular dystrophy

Benign:1

Aug 04, 2024

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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

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

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

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

M_CAP

Benign

0.022

MetaRNN

Benign

0.060

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

MetaSVM

Benign

-1.0

PhyloP100

2.3

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.048

Sift

Benign

0.92

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

Sift4G

Benign

0.82

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

Polyphen

0.075, 0.66, 0.11, 0.0010

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

Vest4

0.051, 0.056, 0.070, 0.044, 0.048, 0.062, 0.031, 0.052

MutPred

0.36

.;.;.;.;.;.;.;Loss of phosphorylation at T2583 (P = 0.0394);.;

MVP

0.51

MPC

0.034

ClinPred

0.12

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.22

Mutation Taster

=98/2

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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rs773656507

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