X-32441209-C-T
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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
NM_004006.3 missense
Scores
2
3
11
Clinical Significance
Conservation
PhyloP100: 5.59
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]
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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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.3892G>A | p.Gly1298Arg | missense_variant | 28/79 | 1 | NM_004006.3 | ENSP00000354923.3 |
Frequencies
GnomAD3 genomes AF: 0.0000810 AC: 9AN: 111095Hom.: 0 Cov.: 23 AF XY: 0.0000896 AC XY: 3AN XY: 33465
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GnomAD3 exomes AF: 0.0000602 AC: 11AN: 182693Hom.: 0 AF XY: 0.0000889 AC XY: 6AN XY: 67459
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GnomAD4 exome AF: 0.0000319 AC: 35AN: 1095971Hom.: 0 Cov.: 29 AF XY: 0.0000331 AC XY: 12AN XY: 362129
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GnomAD4 genome AF: 0.0000810 AC: 9AN: 111095Hom.: 0 Cov.: 23 AF XY: 0.0000896 AC XY: 3AN XY: 33465
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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 submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 06, 2015 | The 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 submitter | clinical testing | Blueprint Genetics | Dec 02, 2015 | - - |
Duchenne muscular dystrophy Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 16, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2021 | This 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;N
REVEL
Benign
Sift
Benign
.;T;.;T
Sift4G
Benign
T;T;T;T
Polyphen
1.0
.;D;.;.
Vest4
MutPred
0.34
.;.;Gain of methylation at G1298 (P = 0.073);Gain of methylation at G1298 (P = 0.073);
MVP
MPC
0.077
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at