rs1553926818

Positions:

• chr4-99591734-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001386140.1(MTTP):​c.708_709delCA​(p.His236fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTTP NM_001386140.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-99591734-AAC-A is Pathogenic according to our data. Variant chr4-99591734-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 435905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.708_709delCA	p.His236fs	frameshift_variant	6/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.708_709delCA	p.His236fs	frameshift_variant	7/19		NP_000244.2
MTTP	NM_001300785.2	c.459_460delCA	p.His153fs	frameshift_variant	6/18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.708_709delCA	p.His236fs	frameshift_variant	6/18	1	NM_001386140.1	ENSP00000265517.5
MTTP	ENST00000457717.6	c.708_709delCA	p.His236fs	frameshift_variant	7/19	5		ENSP00000400821.1
MTTP	ENST00000511045.6	c.459_460delCA	p.His153fs	frameshift_variant	6/18	2		ENSP00000427679.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461122 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Abetalipoproteinaemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 02, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 01, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MTTP are known to be pathogenic (PMID: 8533758, 9671739). This variant has not been reported in the literature in individuals with MTTP-related conditions. ClinVar contains an entry for this variant (Variation ID: 435905). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.His236Glnfs*11) in the MTTP gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1553926818; hg19: chr4-100512891;