rs1553926818

Variant names:

• chr4-99591734-AAC-A
• rs1553926818
• NM_001386140.1:c.708_709delCA

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.His236GlnfsTer11) 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 rank	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.708_709delCA	p.His236GlnfsTer11	frameshift_variant	Exon 6 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.708_709delCA	p.His236GlnfsTer11	frameshift_variant	Exon 7 of 19		NP_000244.2
MTTP	NM_001300785.2	c.459_460delCA	p.His153GlnfsTer11	frameshift_variant	Exon 6 of 18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.708_709delCA	p.His236GlnfsTer11	frameshift_variant	Exon 6 of 18	1	NM_001386140.1	ENSP00000265517.5
MTTP	ENST00000457717.6	c.708_709delCA	p.His236GlnfsTer11	frameshift_variant	Exon 7 of 19	5		ENSP00000400821.1
MTTP	ENST00000511045.6	c.459_460delCA	p.His153GlnfsTer11	frameshift_variant	Exon 6 of 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

Jun 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Apr 01, 2019

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.His236Glnfs*11) in the MTTP gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). 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). Loss-of-function variants in MTTP are known to be pathogenic (PMID: 8533758, 9671739). For these reasons, this variant has been classified as Pathogenic. -

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;