Variant X-32644139-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000357033.9(DMD):c.1324C>G(p.Gln442Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

DMD
ENST00000357033.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.56

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in ENST00000357033.9

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.1324C>G	p.Gln442Glu	missense_variant	11/79	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.1324C>G	p.Gln442Glu	missense_variant	11/79	1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000560

AC:

AN:

178552

Hom.:

AF XY:

0.00

AC XY:

AN XY:

63458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000733

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:

9.15e-7

AC:

AN:

1093006

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358846

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Duchenne muscular dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2023

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 442 of the DMD protein (p.Gln442Glu). This variant is present in population databases (no rsID available, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DMD protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T;.;.;T

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;.;D;D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.69

D;D;D;D;D

MetaSVM

Benign

-0.48

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.2

.;N;.;N;D

REVEL

Benign

0.26

Sift

Uncertain

0.0050

.;D;.;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

0.99, 0.63

.;D;.;.;P

Vest4

0.81

MutPred

0.52

.;.;Loss of MoRF binding (P = 0.0259);Loss of MoRF binding (P = 0.0259);.;

MVP

0.80

MPC

0.031

ClinPred

0.55

GERP RS

5.7

gMVP

0.63

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