Genetic Variant DMD:p.Val374Val (chrX-32644991-C-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004006.3(DMD):c.1122G>C(p.Val374Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,209,476 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V374V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000066 ( 0 hom. 17 hem. )

Consequence

DMD
NM_004006.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.820

Publications

0 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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant X-32644991-C-G is Benign according to our data. Variant chrX-32644991-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 415871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.82 with no splicing effect.

BS2

High AC in GnomAdExome4 at 73 XL,AD gene.

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.1122G>C	p.Val374Val	synonymous	Exon 10 of 79	NP_003997.2
DMD	NM_004009.3		c.1110G>C	p.Val370Val	synonymous	Exon 10 of 79	NP_004000.1
DMD	NM_000109.4		c.1098G>C	p.Val366Val	synonymous	Exon 10 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	ENST00000357033.9	TSL:1 MANE Select	c.1122G>C	p.Val374Val	synonymous	Exon 10 of 79	ENSP00000354923.3
DMD	ENST00000288447.9	TSL:1	c.1098G>C	p.Val366Val	synonymous	Exon 10 of 18	ENSP00000288447.4
DMD	ENST00000447523.1	TSL:1	c.247-71145G>C		intron	N/A	ENSP00000395904.1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111398

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000436

AC:

AN:

183319

AF XY:

0.0000443

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:

0.0000978

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000665

AC:

AN:

1098078

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

363496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30192

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.0000494

AC:

AN:

40506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000796

AC:

AN:

842026

Other (OTH)

AF:

0.0000868

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.0000180

AC:

AN:

111398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30670

American (AMR)

AF:

0.00

AC:

AN:

10412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5981

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53048

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000340

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Duchenne muscular dystrophy (1)

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.0

(source)

DANN

Benign

0.53

PhyloP100

0.82

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over