rs771312947

Positions:

chrX-32699286-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_004006.3(DMD):c.657T>A(p.Asp219Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,201,407 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 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 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000053 ( 0 hom. 21 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0900

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 -9 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

BP4

Computational evidence support a benign effect (MetaRNN=0.10948324).

BP6

Variant X-32699286-A-T is Benign according to our data. Variant chrX-32699286-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580460.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000532 (58/1089771) while in subpopulation EAS AF= 0.00192 (58/30136). AF 95% confidence interval is 0.00153. There are 0 homozygotes in gnomad4_exome. There are 21 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.657T>A	p.Asp219Glu	missense_variant	8/79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.657T>A	p.Asp219Glu	missense_variant	8/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

AF:

0.00000896

AC:

AN:

111636

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33840

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:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

182437

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67321

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

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:

0.0000532

AC:

AN:

1089771

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

355673

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00192

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

AF:

0.00000896

AC:

AN:

111636

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33840

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000282

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 18, 2020

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2022

The p.D219E variant (also known as c.657T>A), located in coding exon 8 of the DMD gene, results from a T to A substitution at nucleotide position 657. The aspartic acid at codon 219 is replaced by glutamic acid, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.0022% (4/182437) total alleles studied, with 1 hemizygotes observed. The highest observed frequency was 0.0289% (4/13828) of East Asian alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

.;D;.;.;D

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.81

T;.;T;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.46

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.43

.;N;.;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.097

.;T;.;T;T

Sift4G

Benign

0.069

T;T;T;T;T

Polyphen

0.0

.;B;.;.;B

Vest4

0.34

MutPred

0.34

.;.;Loss of glycosylation at T220 (P = 0.1337);Loss of glycosylation at T220 (P = 0.1337);.;

MVP

0.80

MPC

0.016

ClinPred

0.035

GERP RS

-1.0

gMVP

0.25

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