X-32441209-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004006.3(DMD):​c.3892G>A​(p.Gly1298Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000365 in 1,207,066 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 3 hem., cov: 23)
Exomes 𝑓: 0.000032 ( 0 hom. 12 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

2
3
11

Clinical Significance

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

Conservation

PhyloP100: 5.59
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1991274).
BP6
Variant X-32441209-C-T is Benign according to our data. Variant chrX-32441209-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222546.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=1}.
BS2
High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DMDNM_004006.3 linkc.3892G>A p.Gly1298Arg missense_variant 28/79 ENST00000357033.9 NP_003997.2 P11532

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DMDENST00000357033.9 linkc.3892G>A p.Gly1298Arg missense_variant 28/791 NM_004006.3 ENSP00000354923.3 A0A075B6G3

Frequencies

GnomAD3 genomes
AF:
0.0000810
AC:
9
AN:
111095
Hom.:
0
Cov.:
23
AF XY:
0.0000896
AC XY:
3
AN XY:
33465
show subpopulations
Gnomad AFR
AF:
0.0000977
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000289
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000740
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000190
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000602
AC:
11
AN:
182693
Hom.:
0
AF XY:
0.0000889
AC XY:
6
AN XY:
67459
show subpopulations
Gnomad AFR exome
AF:
0.000152
Gnomad AMR exome
AF:
0.000146
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000105
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000368
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000319
AC:
35
AN:
1095971
Hom.:
0
Cov.:
29
AF XY:
0.0000331
AC XY:
12
AN XY:
362129
show subpopulations
Gnomad4 AFR exome
AF:
0.0000380
Gnomad4 AMR exome
AF:
0.000114
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000203
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000190
Gnomad4 OTH exome
AF:
0.0000653
GnomAD4 genome
AF:
0.0000810
AC:
9
AN:
111095
Hom.:
0
Cov.:
23
AF XY:
0.0000896
AC XY:
3
AN XY:
33465
show subpopulations
Gnomad4 AFR
AF:
0.0000977
Gnomad4 AMR
AF:
0.000289
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000740
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000190
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000155
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 06, 2015The p.Gly1298Arg variant in DMD has not been previously reported in individuals with cardiomyopathy, but has been identified in 6/86977 total chromosomes (4 hem izygotes) by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org). Glycine (Gly) at position 1298 is not highly conserved in mammals or evolu tionarily distant species and the Chinese hamster carries an arginine (Arg), rai sing the possibility that this change may be tolerated. Additional computational prediction tools suggest that the p.Gly1298Arg variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Gly1298Arg variant is uncertain. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsDec 02, 2015- -
Duchenne muscular dystrophy Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 16, 2023- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 14, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
.;T;.;.
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.89
D;.;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Benign
0.20
T;T;T;T
MetaSVM
Benign
-0.88
T
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.2
.;N;.;N
REVEL
Benign
0.16
Sift
Benign
0.18
.;T;.;T
Sift4G
Benign
0.72
T;T;T;T
Polyphen
1.0
.;D;.;.
Vest4
0.33
MutPred
0.34
.;.;Gain of methylation at G1298 (P = 0.073);Gain of methylation at G1298 (P = 0.073);
MVP
0.66
MPC
0.077
ClinPred
0.16
T
GERP RS
5.3
gMVP
0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750349613; hg19: chrX-32459326; COSMIC: COSV63759742; API