NM_004006.3:c.4213C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004006.3(DMD):​c.4213C>A​(p.Gln1405Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,952 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1405L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

1
6
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.09

Publications

0 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

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37837178).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DMDNM_004006.3 linkc.4213C>A p.Gln1405Lys missense_variant Exon 30 of 79 ENST00000357033.9 NP_003997.2 P11532

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkc.4213C>A p.Gln1405Lys missense_variant Exon 30 of 79 1 NM_004006.3 ENSP00000354923.3 A0A075B6G3

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097952
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
1
AN XY:
363402
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26390
American (AMR)
AF:
0.00
AC:
0
AN:
35202
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
19378
East Asian (EAS)
AF:
0.00
AC:
0
AN:
30175
South Asian (SAS)
AF:
0.00
AC:
0
AN:
54137
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40517
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4136
European-Non Finnish (NFE)
AF:
0.00000119
AC:
1
AN:
841941
Other (OTH)
AF:
0.00
AC:
0
AN:
46076
GnomAD4 genome
Cov.:
22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
.;T;.;.
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;.;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.38
T;T;T;T
MetaSVM
Benign
-0.98
T
PhyloP100
8.1
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.1
.;N;.;N
REVEL
Benign
0.13
Sift
Uncertain
0.025
.;D;.;D
Sift4G
Uncertain
0.014
D;D;D;D
Polyphen
0.46
.;P;.;.
Vest4
0.43
MutPred
0.38
.;.;Gain of ubiquitination at Q1405 (P = 0.009);Gain of ubiquitination at Q1405 (P = 0.009);
MVP
0.62
MPC
0.019
ClinPred
0.79
D
GERP RS
5.7
PromoterAI
0.0070
Neutral
gMVP
0.22
Mutation Taster
=96/4
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs128626247; hg19: chrX-32429889; API