X-31223056-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The NM_004006.3(DMD):c.9352G>A(p.Ala3118Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000828 in 1,207,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3118S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.92

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP6

Variant X-31223056-C-T is Benign according to our data. Variant chrX-31223056-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 811289.

BS2

High AC in GnomAdExome4 at 7 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.9352G>A	p.Ala3118Thr	missense	Exon 64 of 79	NP_003997.2	P11532-1
DMD	NM_004009.3		c.9340G>A	p.Ala3114Thr	missense	Exon 64 of 79	NP_004000.1	P11532
DMD	NM_000109.4		c.9328G>A	p.Ala3110Thr	missense	Exon 64 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.9352G>A	p.Ala3118Thr	missense	Exon 64 of 79	ENSP00000354923.3	P11532-1
DMD	ENST00000378723.7	TSL:1	c.148G>A	p.Ala50Thr	missense	Exon 3 of 17	ENSP00000367997.3	P11532-6
DMD	ENST00000361471.8	TSL:1	c.148G>A	p.Ala50Thr	missense	Exon 3 of 16	ENSP00000354464.4	P11532-5

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112027

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000109

AC:

AN:

183500

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000365

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:

0.00000639

AC:

AN:

1095175

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

360613

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26339

American (AMR)

AF:

0.0000568

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19371

East Asian (EAS)

AF:

0.00

AC:

AN:

30192

South Asian (SAS)

AF:

0.00

AC:

AN:

54084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839307

Other (OTH)

AF:

0.0000217

AC:

AN:

46020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

0.0000268

AC:

AN:

112027

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34187

show subpopulations

African (AFR)

AF:

0.0000974

AC:

AN:

30802

American (AMR)

AF:

0.00

AC:

AN:

10556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3602

South Asian (SAS)

AF:

0.00

AC:

AN:

2640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6103

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53251

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

DMD-related disorder (1)

Duchenne muscular dystrophy (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.36

PhyloP100

6.9

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.24

Sift

Benign

0.23

Sift4G

Benign

0.17

Polyphen

0.60

Vest4

0.70

MVP

0.87

MPC

0.040

ClinPred

0.69

GERP RS

5.2

gMVP

0.36

Mutation Taster

=15/85

disease causing

(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