rs149428656
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP6BS2_Supporting
The NM_004006.3(DMD):āc.295A>Gā(p.Ile99Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,206,699 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 75 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004006.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.295A>G | p.Ile99Val | missense_variant | Exon 5 of 79 | 1 | NM_004006.3 | ENSP00000354923.3 |
Frequencies
GnomAD3 genomes AF: 0.000107 AC: 12AN: 111658Hom.: 0 Cov.: 23 AF XY: 0.0000591 AC XY: 2AN XY: 33832
GnomAD3 exomes AF: 0.0000491 AC: 9AN: 183286Hom.: 0 AF XY: 0.0000295 AC XY: 2AN XY: 67782
GnomAD4 exome AF: 0.000245 AC: 268AN: 1094994Hom.: 0 Cov.: 28 AF XY: 0.000202 AC XY: 73AN XY: 360734
GnomAD4 genome AF: 0.000107 AC: 12AN: 111705Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2AN XY: 33889
ClinVar
Submissions by phenotype
not specified Uncertain:2
Variant summary: DMD c.295A>G (p.Ile99Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 205192 control chromosomes including 3 hemizygotes, predominantly at a frequency of 0.00026 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.295A>G in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 166867). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
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not provided Uncertain:1Benign:1
See Variant Classification Assertion Criteria. -
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Becker muscular dystrophy Uncertain:1
The p.Ile99Val variant in the DMDgene has not been previously reported in association with disease.This variant has been identified in 13/205,192 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/), including in 3 hemizygotes.The isoleucine at position99 is highly evolutionarily conserved and computational tools predict that the p.Ile99Val variant is deleterious; however, the accuracy of in silicoalgorithms is limited.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ile99Valvariant is uncertain;however, population frequency data suggests that this variant is more likely to be benign than pathogenic. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: PP3] -
Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.I99V variant (also known as c.295A>G), located in coding exon 5 of the DMD gene, results from an A to G substitution at nucleotide position 295. The isoleucine at codon 99 is replaced by valine, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.006% (13/205192) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.02% (5/19039) of African/African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Duchenne muscular dystrophy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at