rs201302282

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004006.3(DMD):c.5701G>A(p.Ala1901Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,208,889 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 127 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). Synonymous variant affecting the same amino acid position (i.e. A1901A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00031 ( 0 hom. 122 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 5.06

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23704728).

BP6

Variant X-32343172-C-T is Benign according to our data. Variant chrX-32343172-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180314.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}. Variant chrX-32343172-C-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.5701G>A	p.Ala1901Thr	missense_variant	40/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.5701G>A	p.Ala1901Thr	missense_variant	40/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

111232

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33458

show subpopulations

Gnomad AFR

AF:

0.0000653

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:

0.000302

Gnomad OTH

AF:

0.000672

GnomAD3 exomes

AF:

0.000169

AC:

AN:

183027

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

67643

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000125

Gnomad NFE exome

AF:

0.000306

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000308

AC:

338

AN:

1097605

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

122

AN XY:

363097

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000987

Gnomad4 NFE exome

AF:

0.000378

Gnomad4 OTH exome

AF:

0.000239

GnomAD4 genome

AF:

0.000162

AC:

AN:

111284

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33522

show subpopulations

Gnomad4 AFR

AF:

0.0000651

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000283

Gnomad4 OTH

AF:

0.000664

Alfa

AF:

0.000306

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000710

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 10, 2015	The p.Ala1901Thr variant in DMD has not been previously reported in individuals with cardiomyopathy, but has been identified in 14/47910 European chromosomes (i ncluding 6 hemizygotes) by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; rs201302282). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ala1901Thr variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 02, 2017	- -

Primary dilated cardiomyopathy

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 29, 2014	- -
Likely benign, criteria provided, single submitter	research	Genetics and Genomics Program, Sidra Medicine	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2019

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

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;.;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.44

Sift4G

Benign

0.20

T;T;T;T;D

Polyphen

1.0

.;D;.;.;.

Vest4

0.52

MVP

0.64

MPC

0.016

ClinPred

0.066

GERP RS

6.1

gMVP

0.098

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