rs755681036

Positions:

• chr4-99613133-AT-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.2212del​(p.Ser738LeufsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H737H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MTTP NM_001386140.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.11

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]

(HGNC:):

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 4-99613133-AT-A is Pathogenic according to our data. Variant chr4-99613133-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 495776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99613133-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTTP	NM_001386140.1	c.2212del	p.Ser738LeufsTer10	frameshift_variant	15/18	ENST00000265517.10
MTTP	NM_000253.4	c.2212del	p.Ser738LeufsTer10	frameshift_variant	16/19
MTTP	NM_001300785.2	c.1963del	p.Ser655LeufsTer10	frameshift_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTTP	ENST00000265517.10	c.2212del	p.Ser738LeufsTer10	frameshift_variant	15/18	1	NM_001386140.1	P1
	ENST00000508578.1	n.128+7753del		intron_variant, non_coding_transcript_variant		5
MTTP	ENST00000457717.6	c.2212del	p.Ser738LeufsTer10	frameshift_variant	16/19	5		P1
MTTP	ENST00000511045.6	c.1963del	p.Ser655LeufsTer10	frameshift_variant	15/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460148 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 16, 2023

Variant summary: MTTP c.2212delT (p.Ser738LeufsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 249852 control chromosomes (gnomAD). c.2212delT has been reported in the literature in multiple individuals affected with Abetalipoproteinaemia (Bassen-Kornzweig Syndrome)(examples: Benayoun_2007 and Narcisi_1995). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

This sequence change creates a premature translational stop signal (p.Ser738Leufs*10) in the MTTP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTTP are known to be pathogenic (PMID: 8533758, 9671739). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with abetalipoproteinemia (PMID: 8533758). ClinVar contains an entry for this variant (Variation ID: 495776). 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: rs755681036; hg19: chr4-100534290;