rs111460954
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_005373.3(MPL):c.622C>A(p.Gln208Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,232 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_005373.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPL | NM_005373.3 | c.622C>A | p.Gln208Lys | missense_variant | 4/12 | ENST00000372470.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.622C>A | p.Gln208Lys | missense_variant | 4/12 | 1 | NM_005373.3 | P1 | |
MPL | ENST00000413998.7 | c.601C>A | p.Gln201Lys | missense_variant | 4/12 | 1 | |||
MPL | ENST00000638732.1 | n.622C>A | non_coding_transcript_exon_variant | 4/10 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251440Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461894Hom.: 1 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727248
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152338Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6AN XY: 74500
ClinVar
Submissions by phenotype
MPL-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 11, 2023 | The MPL c.622C>A variant is predicted to result in the amino acid substitution p.Gln208Lys. This variant has been reported in an individual with essential thrombocythemia (Rendo et al. 2022. PubMed ID: 35449633). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-43805172-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Primary myelofibrosis;C1327915:Congenital amegakaryocytic thrombocytopenia;C3275998:Thrombocythemia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 11, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 16, 2021 | - - |
Congenital amegakaryocytic thrombocytopenia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 20, 2020 | - - |
Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 208 of the MPL protein (p.Gln208Lys). This variant is present in population databases (rs111460954, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 134828). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at