NM_005373.3:c.413delT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005373.3(MPL):c.413delT(p.Ile138ThrfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_005373.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MPL | ENST00000372470.9 | c.413delT | p.Ile138ThrfsTer28 | frameshift_variant | Exon 4 of 12 | 1 | NM_005373.3 | ENSP00000361548.3 | ||
MPL | ENST00000413998.7 | c.392delT | p.Ile131ThrfsTer28 | frameshift_variant | Exon 4 of 12 | 1 | ENSP00000414004.3 | |||
MPL | ENST00000638732.1 | n.413delT | non_coding_transcript_exon_variant | Exon 4 of 10 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251068Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135790
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461804Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727204
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Congenital amegakaryocytic thrombocytopenia Pathogenic:1
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Essential thrombocythemia;C1327915:Congenital amegakaryocytic thrombocytopenia Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 528088). This variant has not been reported in the literature in individuals affected with MPL-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Ile138Thrfs*28) in the MPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPL are known to be pathogenic (PMID: 8073287, 11133753). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at