4-99574931-T-TCTGAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001386140.1(MTTP):c.22_23insCTGAA(p.Phe8SerfsTer23) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F8F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTTP NM_001386140.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.73

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 105 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-99574931-T-TCTGAA is Pathogenic according to our data. Variant chr4-99574931-T-TCTGAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1724822.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTTP	NM_001386140.1	c.22_23insCTGAA	p.Phe8SerfsTer23	frameshift_variant	1/18	ENST00000265517.10
MTTP	NM_000253.4	c.22_23insCTGAA	p.Phe8SerfsTer23	frameshift_variant	2/19
MTTP	NM_001300785.2	c.-188-6974_-188-6973insCTGAA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTTP	ENST00000265517.10	c.22_23insCTGAA	p.Phe8SerfsTer23	frameshift_variant	1/18	1	NM_001386140.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abetalipoproteinaemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 28, 2022

NM_000253.2(MTTP):c.22_23ins5(F8Sfs*23) is expected to be pathogenic in the context of abetalipoproteinemia. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in MTTP, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-100496088;