Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004006.3(DMD):c.4125T>C(p.Thr1375Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,209,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 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. T1375T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., 17 hem., cov: 22)

Exomes 𝑓: 0.000069 ( 0 hom. 15 hem. )

Consequence

DMD
NM_004006.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.465

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant X-32411860-A-G is Benign according to our data. Variant chrX-32411860-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.465 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000628 (70/111552) while in subpopulation AFR AF = 0.00224 (69/30744). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 70 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.4125T>C	p.Thr1375Thr	synonymous	Exon 30 of 79	NP_003997.2
DMD	NM_004009.3		c.4113T>C	p.Thr1371Thr	synonymous	Exon 30 of 79	NP_004000.1
DMD	NM_000109.4		c.4101T>C	p.Thr1367Thr	synonymous	Exon 30 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	ENST00000357033.9	TSL:1 MANE Select	c.4125T>C	p.Thr1375Thr	synonymous	Exon 30 of 79	ENSP00000354923.3
DMD	ENST00000378677.6	TSL:5	c.4113T>C	p.Thr1371Thr	synonymous	Exon 30 of 79	ENSP00000367948.2
DMD	ENST00000619831.5	TSL:5	c.93T>C	p.Thr31Thr	synonymous	Exon 2 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes

AF:

0.000628

AC:

AN:

111500

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00225

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000957

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:

0.000197

AC:

AN:

182751

AF XY:

0.000178

show subpopulations

Gnomad AFR exome

AF:

0.00266

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000692

AC:

AN:

1097710

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363180

show subpopulations

African (AFR)

AF:

0.00246

AC:

AN:

26389

American (AMR)

AF:

0.00

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30149

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841759

Other (OTH)

AF:

0.000130

AC:

AN:

46072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000628

AC:

AN:

111552

Hom.:

Cov.:

AF XY:

0.000504

AC XY:

AN XY:

33746

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

30744

American (AMR)

AF:

0.0000956

AC:

AN:

10458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3502

South Asian (SAS)

AF:

0.00

AC:

AN:

2650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53135

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000608

Hom.:

Bravo

AF:

0.000835

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

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

-0.86

CADD

Benign

0.89

(source)

DANN

Benign

0.44

PhyloP100

-0.47

PromoterAI

0.036

Neutral

(source)

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.

rs144329742

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over