rs28928907
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM5PP3_ModeratePP5_Moderate
The NM_005373.3(MPL):c.305G>A(p.Arg102His) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102P) has been classified as Pathogenic.
Frequency
Consequence
NM_005373.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPL | NM_005373.3 | c.305G>A | p.Arg102His | missense_variant | 3/12 | ENST00000372470.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.305G>A | p.Arg102His | missense_variant | 3/12 | 1 | NM_005373.3 | P1 | |
MPL | ENST00000413998.7 | c.284G>A | p.Arg95His | missense_variant | 3/12 | 1 | |||
MPL | ENST00000638732.1 | n.305G>A | non_coding_transcript_exon_variant | 3/10 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727246
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 102 of the MPL protein (p.Arg102His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive congenital amegakaryocytic thrombocytopenia (PMID: 32703794). ClinVar contains an entry for this variant (Variation ID: 988868). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPL protein function. This variant disrupts the p.Arg102 amino acid residue in MPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11972523, 16470591, 21659346, 28859041). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1
Uncertain significance, no assertion criteria provided | research | Birmingham Platelet Group; University of Birmingham | May 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at