rs3816873

Positions:

• chr4-99583507-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001386140.1(MTTP):​c.383T>C​(p.Ile128Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,613,128 control chromosomes in the GnomAD database, including 55,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5382 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49652 hom.)
• Consequence: MTTP NM_001386140.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.741

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.649328E-4).
• BP6: Variant 4-99583507-T-C is Benign according to our data. Variant chr4-99583507-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 14242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99583507-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1	c.383T>C	p.Ile128Thr	missense_variant	3/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4	c.383T>C	p.Ile128Thr	missense_variant	4/19		NP_000244.2
MTTP	NM_001300785.2	c.134T>C	p.Ile45Thr	missense_variant	3/18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10	c.383T>C	p.Ile128Thr	missense_variant	3/18	1	NM_001386140.1	ENSP00000265517.5
MTTP	ENST00000422897.6	c.383T>C	p.Ile128Thr	missense_variant	3/3	1		ENSP00000407350.2
MTTP	ENST00000457717.6	c.383T>C	p.Ile128Thr	missense_variant	4/19	5		ENSP00000400821.1
MTTP	ENST00000511045.6	c.134T>C	p.Ile45Thr	missense_variant	3/18	2		ENSP00000427679.2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39787 AN: 151904 Hom.: 5374 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.248 AC: 61707 AN: 248600 Hom.: 8316 AF XY: 0.255 AC XY: 34436 AN XY: 134784

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.137

Gnomad SAS exome AF: 0.346

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.259

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.257 AC: 374829 AN: 1461106 Hom.: 49652 Cov.: 35 AF XY: 0.260 AC XY: 189092 AN XY: 726840

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.342

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.255

Gnomad4 OTH exome AF: 0.269

GnomAD4 genome AF: 0.262 AC: 39818 AN: 152022 Hom.: 5382 Cov.: 32 AF XY: 0.261 AC XY: 19359 AN XY: 74306

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.399

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.298

Alfa AF: 0.265 Hom.: 14260

Bravo AF: 0.261

TwinsUK AF: 0.254 AC: 940

ALSPAC AF: 0.271 AC: 1043

ESP6500AA AF: 0.272 AC: 1197

ESP6500EA AF: 0.258 AC: 2218

ExAC AF: 0.249 AC: 30226

Asia WGS AF: 0.291 AC: 1008 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.265

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 05, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2014	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 21438662, 16617174, 16721486, 30782561, 33111339) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Abetalipoproteinaemia Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Abetalipoproteinaemia;C4552048:Metabolic syndrome X Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 11, 2022

- -

RECLASSIFIED - MTTP POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.011	T;.;T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.71	T;T;.;T;T
MetaRNN	Benign	0.00056	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;L;L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.71	N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.64	T;T;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.0020, 0.0	.;B;B;B;.
Vest4		0.026, 0.018, 0.017, 0.027
MPC		0.30
ClinPred		0.0061	T
GERP RS		4.1
Varity_R		0.074
gMVP		0.24

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: rs3816873; hg19: chr4-100504664; COSMIC: COSV55504606; COSMIC: COSV55504606;