NM_004006.3:c.1309G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM5BP6BS2_Supporting

The NM_004006.3(DMD):c.1309G>C(p.Ala437Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000912 in 1,206,681 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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. A437D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 2 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.09

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: 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: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-32644153-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP6

Variant X-32644154-C-G is Benign according to our data. Variant chrX-32644154-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455860.

BS2

High AC in GnomAdExome4 at 9 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
DMD	NM_004006.3	MANE Select	c.1309G>C	p.Ala437Pro	missense	Exon 11 of 79	NP_003997.2
DMD	NM_004009.3		c.1297G>C	p.Ala433Pro	missense	Exon 11 of 79	NP_004000.1
DMD	NM_000109.4		c.1285G>C	p.Ala429Pro	missense	Exon 11 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	ENST00000357033.9	TSL:1 MANE Select	c.1309G>C	p.Ala437Pro	missense	Exon 11 of 79	ENSP00000354923.3
DMD	ENST00000288447.9	TSL:1	c.1285G>C	p.Ala429Pro	missense	Exon 11 of 18	ENSP00000288447.4
DMD	ENST00000447523.1	TSL:1	c.247-70308G>C		intron	N/A	ENSP00000395904.1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111443

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

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:

0.0000443

AC:

AN:

180782

AF XY:

0.0000306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1095238

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

360832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26298

American (AMR)

AF:

0.000171

AC:

AN:

34992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19293

East Asian (EAS)

AF:

0.00

AC:

AN:

30153

South Asian (SAS)

AF:

0.00

AC:

AN:

53598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40391

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840404

Other (OTH)

AF:

0.0000217

AC:

AN:

45981

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

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:

0.0000179

AC:

AN:

111443

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

33635

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30683

American (AMR)

AF:

0.000191

AC:

AN:

10447

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2671

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53025

Other (OTH)

AF:

0.00

AC:

AN:

1502

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

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

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.60

PhyloP100

4.1

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

REVEL

Benign

0.25

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.98

Vest4

0.77

MutPred

0.73

Gain of disorder (P = 0.0325)

MVP

0.77

MPC

0.12

ClinPred

0.25

GERP RS

5.0

gMVP

0.78

Mutation Taster

=55/45

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

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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