Genetic Variant DMD:p.Gln1432Gln (chrX-32390119-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7

The NM_004006.3(DMD):c.4296G>A(p.Gln1432Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

DMD
NM_004006.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.229

Publications

2 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: Benign. The variant received -9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant X-32390119-C-T is Benign according to our data. Variant chrX-32390119-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 761383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.229 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	NM_004006.3	MANE Select	c.4296G>A	p.Gln1432Gln	synonymous	Exon 31 of 79	NP_003997.2
DMD	NM_004009.3		c.4284G>A	p.Gln1428Gln	synonymous	Exon 31 of 79	NP_004000.1
DMD	NM_000109.4		c.4272G>A	p.Gln1424Gln	synonymous	Exon 31 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	ENST00000357033.9	TSL:1 MANE Select	c.4296G>A	p.Gln1432Gln	synonymous	Exon 31 of 79	ENSP00000354923.3
DMD	ENST00000378677.6	TSL:5	c.4284G>A	p.Gln1428Gln	synonymous	Exon 31 of 79	ENSP00000367948.2
DMD	ENST00000619831.5	TSL:5	c.264G>A	p.Gln88Gln	synonymous	Exon 3 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111965

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

182711

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000725

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097201

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362707

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26378

American (AMR)

AF:

0.00

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.00

AC:

AN:

30153

South Asian (SAS)

AF:

0.00

AC:

AN:

54119

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841298

Other (OTH)

AF:

0.00

AC:

AN:

46061

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 Het

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

AF:

0.00000893

AC:

AN:

112019

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34181

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30856

American (AMR)

AF:

0.00

AC:

AN:

10558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.000282

AC:

AN:

3541

South Asian (SAS)

AF:

0.00

AC:

AN:

2688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53197

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Dec 13, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jul 24, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

4.1

(source)

DANN

Benign

0.57

PhyloP100

0.23

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over