rs146064714

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

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

MTTP
NM_001386140.1 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.15
Variant links:
Genes affected
MTTP (HGNC:7467): (microsomal triglyceride transfer protein) MTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Protein disulfide isomerase (PDI) completes the heterodimeric microsomal triglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. Mutations in MTP can cause abetalipoproteinemia. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0343 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-99622756-G-T is Pathogenic according to our data. Variant chr4-99622756-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99622756-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTTPNM_001386140.1 linkc.2593G>T p.Gly865* stop_gained Exon 18 of 18 ENST00000265517.10 NP_001373069.1
MTTPNM_000253.4 linkc.2593G>T p.Gly865* stop_gained Exon 19 of 19 NP_000244.2 P55157-1
MTTPNM_001300785.2 linkc.2344G>T p.Gly782* stop_gained Exon 18 of 18 NP_001287714.2 P55157B7Z7X3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTTPENST00000265517.10 linkc.2593G>T p.Gly865* stop_gained Exon 18 of 18 1 NM_001386140.1 ENSP00000265517.5 P55157-1
MTTPENST00000457717.6 linkc.2593G>T p.Gly865* stop_gained Exon 19 of 19 5 ENSP00000400821.1 P55157-1
MTTPENST00000511045.6 linkc.2344G>T p.Gly782* stop_gained Exon 18 of 18 2 ENSP00000427679.2 E9PBP6
ENSG00000248676ENST00000508578.1 linkn.33-1774C>A intron_variant Intron 1 of 3 5

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000119
AC:
30
AN:
251438
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00268
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000636
AC:
93
AN:
1461830
Hom.:
0
Cov.:
31
AF XY:
0.0000729
AC XY:
53
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00253
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000179
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Abetalipoproteinaemia Pathogenic:5
Jul 24, 2017
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jun 19, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 26, 2023
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:2
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 12, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
39
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.55
GERP RS
6.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146064714; hg19: chr4-100543913; API