dbSNP rs142441725: DMD:p.Glu1874Lys (chrX-32343253-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004006.3(DMD):c.5620G>A(p.Glu1874Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000204 in 1,206,757 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 67 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 34 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 0 hom. 33 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.82

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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014114022).

BP6

Variant X-32343253-C-T is Benign according to our data. Variant chrX-32343253-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00105 (117/111033) while in subpopulation AFR AF = 0.00363 (111/30542). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 117 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	UniProt
DMD	NM_004006.3	MANE Select	c.5620G>A	p.Glu1874Lys	missense	Exon 40 of 79	NP_003997.2	P11532-1
DMD	NM_004009.3		c.5608G>A	p.Glu1870Lys	missense	Exon 40 of 79	NP_004000.1	P11532
DMD	NM_000109.4		c.5596G>A	p.Glu1866Lys	missense	Exon 40 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMD	ENST00000357033.9	TSL:1 MANE Select	c.5620G>A	p.Glu1874Lys	missense	Exon 40 of 79	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.5608G>A	p.Glu1870Lys	missense	Exon 40 of 79	ENSP00000367948.2	P11532-11
DMD	ENST00000619831.5	TSL:5	c.1588G>A	p.Glu530Lys	missense	Exon 12 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

117

AN:

110984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00364

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000482

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000284

AC:

AN:

182835

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00342

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.000118

AC:

129

AN:

1095724

Hom.:

Cov.:

AF XY:

0.0000913

AC XY:

AN XY:

361286

show subpopulations

African (AFR)

AF:

0.00365

AC:

AN:

26332

American (AMR)

AF:

0.000227

AC:

AN:

35171

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19352

East Asian (EAS)

AF:

0.00

AC:

AN:

30136

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00000476

AC:

AN:

840034

Other (OTH)

AF:

0.000435

AC:

AN:

46006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00105

AC:

117

AN:

111033

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

33289

show subpopulations

African (AFR)

AF:

0.00363

AC:

111

AN:

30542

American (AMR)

AF:

0.000481

AC:

AN:

10391

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2628

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2627

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52971

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.000960

ESP6500AA

AF:

0.00391

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000272

AC:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 3B (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

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.81

PhyloP100

6.8

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.87

REVEL

Benign

0.18

Sift

Benign

0.15

Sift4G

Uncertain

0.042

Polyphen

0.99

Vest4

0.45

MVP

0.60

MPC

0.044

ClinPred

0.052

GERP RS

5.9

gMVP

0.35

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over