dbSNP rs1057521321: DMD:p.Asn26Asp (chrX-33020156-T-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PP3_StrongBP6

The NM_004006.3(DMD):c.76A>G(p.Asn26Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.94

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a region_of_interest Actin-binding (size 239) in uniprot entity DMD_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004006.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

BP6

Variant X-33020156-T-C is Benign according to our data. Variant chrX-33020156-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382300.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.76A>G	p.Asn26Asp	missense_variant	Exon 2 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.76A>G	p.Asn26Asp	missense_variant	Exon 2 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1077167

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

346435

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jun 28, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

.;D;.;.;.;.;D

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;.;D;D;T;T;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.6

.;D;.;D;N;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0080

.;D;.;D;T;D;D

Sift4G

Uncertain

0.011

D;D;D;D;D;D;D

Polyphen

1.0, 0.25

.;D;.;.;.;.;B

Vest4

0.90

MutPred

0.91

.;.;Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);Loss of MoRF binding (P = 0.0497);.;

MVP

0.99

MPC

0.016

ClinPred

0.72

GERP RS

5.2

gMVP

0.91

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