rs2306985

Positions:

chr4-99594865-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001386140.1(MTTP):c.891C>G(p.His297Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,612,596 control chromosomes in the GnomAD database, including 130,556 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 0.47 ( 19562 hom., cov: 32)

Exomes 𝑓: 0.38 ( 110994 hom. )

Consequence

MTTP
NM_001386140.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.413

Variant links:

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]

MTTP links:

ENSG00000248676 (HGNC:):

ENSG00000248676 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.160288E-6).

BP6

Variant 4-99594865-C-G is Benign according to our data. Variant chr4-99594865-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99594865-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTTP	NM_001386140.1 linkuse as main transcript	c.891C>G	p.His297Gln	missense_variant	7/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 linkuse as main transcript	c.891C>G	p.His297Gln	missense_variant	8/19		NP_000244.2	P55157-1
MTTP	NM_001300785.2 linkuse as main transcript	c.642C>G	p.His214Gln	missense_variant	7/18		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MTTP	ENST00000265517.10 linkuse as main transcript	c.891C>G	p.His297Gln	missense_variant	7/18	1	NM_001386140.1	ENSP00000265517.5	P55157-1
MTTP	ENST00000457717.6 linkuse as main transcript	c.891C>G	p.His297Gln	missense_variant	8/19	5		ENSP00000400821.1	P55157-1
MTTP	ENST00000511045.6 linkuse as main transcript	c.642C>G	p.His214Gln	missense_variant	7/18	2		ENSP00000427679.2	E9PBP6
ENSG00000248676	ENST00000508578.1 linkuse as main transcript	n.293G>C		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

71127

AN:

151838

Hom.:

19526

Cov.:

show subpopulations

Gnomad AFR

AF:

0.744

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.575

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.416

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.458

GnomAD3 exomes

AF:

0.394

AC:

99042

AN:

251152

Hom.:

22459

AF XY:

0.393

AC XY:

53327

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.759

Gnomad AMR exome

AF:

0.265

Gnomad ASJ exome

AF:

0.579

Gnomad EAS exome

AF:

0.648

Gnomad SAS exome

AF:

0.419

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.353

Gnomad OTH exome

AF:

0.390

GnomAD4 exome

AF:

0.377

AC:

550719

AN:

1460640

Hom.:

110994

Cov.:

AF XY:

0.378

AC XY:

274945

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.770

Gnomad4 AMR exome

AF:

0.277

Gnomad4 ASJ exome

AF:

0.575

Gnomad4 EAS exome

AF:

0.677

Gnomad4 SAS exome

AF:

0.422

Gnomad4 FIN exome

AF:

0.210

Gnomad4 NFE exome

AF:

0.356

Gnomad4 OTH exome

AF:

0.404

GnomAD4 genome

AF:

0.469

AC:

71206

AN:

151956

Hom.:

19562

Cov.:

AF XY:

0.462

AC XY:

34332

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.745

Gnomad4 AMR

AF:

0.363

Gnomad4 ASJ

AF:

0.575

Gnomad4 EAS

AF:

0.632

Gnomad4 SAS

AF:

0.414

Gnomad4 FIN

AF:

0.206

Gnomad4 NFE

AF:

0.351

Gnomad4 OTH

AF:

0.461

Alfa

AF:

0.394

Hom.:

9722

Bravo

AF:

0.492

TwinsUK

AF:

0.361

AC:

1339

ALSPAC

AF:

0.366

AC:

1409

ESP6500AA

AF:

0.735

AC:

3237

ESP6500EA

AF:

0.364

AC:

3130

ExAC

AF:

0.403

AC:

48867

Asia WGS

AF:

0.456

AC:

1587

AN:

3478

EpiCase

AF:

0.371

EpiControl

AF:

0.379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Abetalipoproteinaemia

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

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: 30782561, 27487388, 26458397) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2019	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.9

DANN

Benign

0.44

DEOGEN2

Benign

0.088

.;T;T

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.015

T;.;T

MetaRNN

Benign

0.0000022

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

.;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

1.0

N;N;N

REVEL

Benign

0.039

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.011

MutPred

0.099

Gain of relative solvent accessibility (P = 0.0999);.;.;

MPC

0.23

ClinPred

0.0016

GERP RS

-2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over