NM_001386140.1:c.2593G>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001386140.1(MTTP):c.2593G>T(p.Gly865*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,010 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 Pathogenic (★★).
Frequency
Consequence
NM_001386140.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MTTP | NM_001386140.1 | c.2593G>T | p.Gly865* | stop_gained | Exon 18 of 18 | ENST00000265517.10 | NP_001373069.1 | |
MTTP | NM_000253.4 | c.2593G>T | p.Gly865* | stop_gained | Exon 19 of 19 | NP_000244.2 | ||
MTTP | NM_001300785.2 | c.2344G>T | p.Gly782* | stop_gained | Exon 18 of 18 | NP_001287714.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MTTP | ENST00000265517.10 | c.2593G>T | p.Gly865* | stop_gained | Exon 18 of 18 | 1 | NM_001386140.1 | ENSP00000265517.5 | ||
MTTP | ENST00000457717.6 | c.2593G>T | p.Gly865* | stop_gained | Exon 19 of 19 | 5 | ENSP00000400821.1 | |||
MTTP | ENST00000511045.6 | c.2344G>T | p.Gly782* | stop_gained | Exon 18 of 18 | 2 | ENSP00000427679.2 | |||
ENSG00000248676 | ENST00000508578.1 | n.33-1774C>A | intron_variant | Intron 1 of 3 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251438Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135884
GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53AN XY: 727210
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74344
ClinVar
Submissions by phenotype
Abetalipoproteinaemia Pathogenic:5
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Variant summary: The MTTP c.2593G>T (p.Gly865X) variant results in a premature termination codon, predicted to cause a truncated or absent MTTP protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 11/122676 control chromosomes at a frequency of 0.0000897, which does not exceed the estimated maximal expected allele frequency of a pathogenic MTTP variant (0.0010607). In the Gnomad control database which has additional ethnic subgroups, almost all carriers for this variant were of Ashkenazi Jewish origin, which supports literature evidence that this variant may be an AJ founder mutation (Benayoun_2007). The variant has been reported in numerous individuals in the literature in the homozygous state, and has been reported to result in the complete absence of MTP activity in in vitro studies and patient intestinal biopsy samples (Ricci_1995). Taken together, this variant is classified as pathogenic. -
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not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gly865*) in the MTTP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MTTP protein. This variant is present in population databases (rs146064714, gnomAD 0.3%). This premature translational stop signal has been observed in individuals with MTTP-related conditions and abetalipoproteinaemia (PMID: 7782284, 8533758, 10679949, 17275380, 20592474, 27271787). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14243). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MTTP function (PMID: 7782284). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate disruption of the normal binding of the MTP protein with protein disulfide isomerase (PDI), indicating that the last 30 amino acid residues are required for the formation of the MTP-PDI complex (Ricci et al., 1995; Rehberg et al., 1996); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost; This variant is associated with the following publications: (PMID: 27415407, 8939939, 7782284, 25552696, 27271787, 23475612, 23556456, 10679949, 31589614, 32041611, 17275380, 20592474) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at