NM_004006.3:c.1225A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004006.3(DMD):​c.1225A>G​(p.Thr409Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,603 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T409S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0270

Publications

6 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.073453546).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DMDNM_004006.3 linkc.1225A>G p.Thr409Ala missense_variant Exon 11 of 79 ENST00000357033.9 NP_003997.2 P11532

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkc.1225A>G p.Thr409Ala missense_variant Exon 11 of 79 1 NM_004006.3 ENSP00000354923.3 A0A075B6G3

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1097603
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
1
AN XY:
363035
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26392
American (AMR)
AF:
0.00
AC:
0
AN:
35190
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19372
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30193
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54136
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40494
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4135
European-Non Finnish (NFE)
AF:
0.00000238
AC:
2
AN:
841616
Other (OTH)
AF:
0.00
AC:
0
AN:
46075
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<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
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Duchenne muscular dystrophy Uncertain:1
Aug 26, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces threonine with alanine at codon 409 of the DMD protein (p.Thr409Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DMD-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.94
CADD
Benign
5.9
DANN
Benign
0.97
DEOGEN2
Benign
0.22
.;T;.;.;T
FATHMM_MKL
Benign
0.072
N
LIST_S2
Benign
0.42
T;.;T;T;T
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.073
T;T;T;T;T
MetaSVM
Benign
-1.0
T
PhyloP100
-0.027
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.010
.;N;.;N;N
REVEL
Benign
0.038
Sift
Benign
0.22
.;T;.;T;T
Sift4G
Benign
0.51
T;T;T;T;T
Polyphen
0.0
.;B;.;.;B
Vest4
0.12
MutPred
0.41
.;.;Loss of methylation at K411 (P = 0.1453);Loss of methylation at K411 (P = 0.1453);.;
MVP
0.44
MPC
0.017
ClinPred
0.026
T
GERP RS
0.29
gMVP
0.10
Mutation Taster
=96/4
polymorphism

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

Other links and lift over

dbSNP: rs34155804; hg19: chrX-32662355; API