rs138145424

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.2539A>G(p.Thr847Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000678 in 1,209,064 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., 12 hem., cov: 24)

Exomes 𝑓: 0.000044 ( 0 hom. 14 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.84

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.063479155).

BP6

Variant X-32491360-T-C is Benign according to our data. Variant chrX-32491360-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195493.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000437 (48/1097423) while in subpopulation AFR AF= 0.00136 (36/26387). AF 95% confidence interval is 0.00101. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.2539A>G	p.Thr847Ala	missense_variant	20/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.2539A>G	p.Thr847Ala	missense_variant	20/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

111584

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

AN XY:

33766

show subpopulations

Gnomad AFR

AF:

0.000881

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000287

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:

0.0000376

Gnomad OTH

AF:

0.000663

GnomAD3 exomes

AF:

0.0000654

AC:

AN:

183496

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

67942

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000437

AC:

AN:

1097423

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

362801

show subpopulations

Gnomad4 AFR exome

AF:

0.00136

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000305

AC:

AN:

111641

Hom.:

Cov.:

AF XY:

0.000355

AC XY:

AN XY:

33833

show subpopulations

Gnomad4 AFR

AF:

0.000912

Gnomad4 AMR

AF:

0.000286

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.000655

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 28, 2015

The p.Thr847Ala variant in DMD has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 4/8508 African chromosomes, inclu ding one male, by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs138145424). Computational prediction tools and conservation an alysis suggest that this variant may not impact the protein, though this informa tion is not predictive enough to rule out pathogenicity. In summary, the clinica l significance of the p.Thr847Ala variant is uncertain. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2020

This alteration is classified as likely 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Benign

0.90

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.77

T;.;T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.063

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

Sift4G

Benign

0.74

T;T;T;T

Polyphen

0.12

.;B;.;.

Vest4

0.32

MVP

0.62

MPC

0.076

ClinPred

0.030

GERP RS

3.6

gMVP

0.066

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

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