rs28730837
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_000250.2(MPO):c.995C>T(p.Ala332Val) variant causes a missense change. The variant allele was found at a frequency of 0.0143 in 1,613,622 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000250.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MPO | ENST00000225275.4 | c.995C>T | p.Ala332Val | missense_variant | Exon 7 of 12 | 1 | NM_000250.2 | ENSP00000225275.3 | ||
MPO | ENST00000578493.2 | n.270C>T | non_coding_transcript_exon_variant | Exon 2 of 7 | 3 | |||||
MPO | ENST00000699291.1 | n.281C>T | non_coding_transcript_exon_variant | Exon 2 of 6 | ENSP00000514272.1 |
Frequencies
GnomAD3 genomes AF: 0.0112 AC: 1703AN: 152240Hom.: 31 Cov.: 32
GnomAD3 exomes AF: 0.0124 AC: 3112AN: 250932Hom.: 41 AF XY: 0.0122 AC XY: 1657AN XY: 135680
GnomAD4 exome AF: 0.0146 AC: 21327AN: 1461264Hom.: 222 Cov.: 32 AF XY: 0.0141 AC XY: 10245AN XY: 726956
GnomAD4 genome AF: 0.0112 AC: 1703AN: 152358Hom.: 31 Cov.: 32 AF XY: 0.0121 AC XY: 901AN XY: 74512
ClinVar
Submissions by phenotype
Myeloperoxidase deficiency Pathogenic:1Uncertain:2Benign:1
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NM_000250.1:c.995C>T in the MPO gene has an allele frequency of 0.043 in European (Finnish) subpopulation in the gnomAD database. Mutations in the MPO gene lead to Hereditary myeloperoxidase (MPO) deficiency in an autosomal recessive manner. Although a number of 45 homozygous occurrences is observed in the gnomAD database, the majority patients with myeloperoxidase deficiency are asymptomatic clinically except if they are also diabetic. Therefore we determined not to adapt this as a strong benign evidence. Marchetti et al. identified a individual with a partial myeloperoxidase deficiency, harboring the compound heterozygote for this variant and c.1715T>G (PMID: 15108282). Conservatively, we interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PM3, PP4, BS1. -
The heterozygous p.Ala332Val variant in MPO has been identified in 2 individuals with myeloperoxidase deficiency (PMID: 15108282), but has also been identified in >4% of European (Finnish) chromosomes and 27 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive myeloperoxidase deficiency. -
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not provided Benign:1
MPO: BS1, BS2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at