X-32365175-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_004006.3(DMD):c.4870C>G(p.Gln1624Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,573 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 2 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.66

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
dilated cardiomyopathy 3B
Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
Duchenne and Becker muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Duchenne muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
progressive muscular dystrophy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22372195).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL,AD geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.4870C>G	p.Gln1624Glu	missense_variant	Exon 35 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.4870C>G	p.Gln1624Glu	missense_variant	Exon 35 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183021

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097573

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

363099

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26377

American (AMR)

AF:

0.00

AC:

AN:

35173

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30169

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40469

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841694

Other (OTH)

AF:

0.00

AC:

AN:

46052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Duchenne muscular dystrophy

Uncertain:1

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1624 of the DMD protein (p.Gln1624Glu). This variant is present in population databases (rs762250680, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with DMD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

Cardiovascular phenotype

Uncertain:1

Sep 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q1624E variant (also known as c.4870C>G), located in coding exon 35 of the DMD gene, results from a C to G substitution at nucleotide position 4870. The glutamine at codon 1624 is replaced by glutamic acid, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/183021) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.002% (2/81678) of European (non-Finnish) alleles. This amino acid position is not well 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;T;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;.;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

6.7

PrimateAI

Benign

0.37

PROVEAN

Benign

0.0

.;N;.;N;N

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;.;D;T

Sift4G

Benign

0.13

T;T;T;T;T

Vest4

0.21

ClinPred

0.24

GERP RS

4.8

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over