chr4-99583418-G-C

Position:

chr4-99583418-G-C

Variant summary

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

The NM_001386140.1(MTTP):c.294G>C(p.Glu98Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0509 in 1,613,268 control chromosomes in the GnomAD database, including 3,733 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 1009 hom., cov: 32)

Exomes 𝑓: 0.047 ( 2724 hom. )

Consequence

MTTP
NM_001386140.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.225

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:

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=0.001547575).

BP6

Variant 4-99583418-G-C is Benign according to our data. Variant chr4-99583418-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 347021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-99583418-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MTTP	NM_001386140.1 linkuse as main transcript	c.294G>C	p.Glu98Asp	missense_variant	3/18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 linkuse as main transcript	c.294G>C	p.Glu98Asp	missense_variant	4/19		NP_000244.2
MTTP	NM_001300785.2 linkuse as main transcript	c.45G>C	p.Glu15Asp	missense_variant	3/18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 linkuse as main transcript	c.294G>C	p.Glu98Asp	missense_variant	3/18	1	NM_001386140.1	ENSP00000265517	P1	P55157-1

Frequencies

GnomAD3 genomes

AF:

0.0856

AC:

13003

AN:

151976

Hom.:

1005

Cov.:

show subpopulations

Gnomad AFR

AF:

0.192

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0641

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.0472

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0345

Gnomad OTH

AF:

0.0670

GnomAD3 exomes

AF:

0.0592

AC:

14750

AN:

249084

Hom.:

801

AF XY:

0.0546

AC XY:

7369

AN XY:

135014

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.0542

Gnomad ASJ exome

AF:

0.0499

Gnomad EAS exome

AF:

0.190

Gnomad SAS exome

AF:

0.0405

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.0343

Gnomad OTH exome

AF:

0.0442

GnomAD4 exome

AF:

0.0473

AC:

69149

AN:

1461174

Hom.:

2724

Cov.:

AF XY:

0.0466

AC XY:

33854

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.197

Gnomad4 AMR exome

AF:

0.0533

Gnomad4 ASJ exome

AF:

0.0501

Gnomad4 EAS exome

AF:

0.212

Gnomad4 SAS exome

AF:

0.0408

Gnomad4 FIN exome

AF:

0.0207

Gnomad4 NFE exome

AF:

0.0378

Gnomad4 OTH exome

AF:

0.0572

GnomAD4 genome

AF:

0.0856

AC:

13024

AN:

152094

Hom.:

1009

Cov.:

AF XY:

0.0837

AC XY:

6220

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.192

Gnomad4 AMR

AF:

0.0639

Gnomad4 ASJ

AF:

0.0493

Gnomad4 EAS

AF:

0.187

Gnomad4 SAS

AF:

0.0468

Gnomad4 FIN

AF:

0.0169

Gnomad4 NFE

AF:

0.0345

Gnomad4 OTH

AF:

0.0720

Alfa

AF:

0.0458

Hom.:

202

Bravo

AF:

0.0937

TwinsUK

AF:

0.0426

AC:

158

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.186

AC:

818

ESP6500EA

AF:

0.0408

AC:

351

ExAC

AF:

0.0604

AC:

7329

Asia WGS

AF:

0.109

AC:

376

AN:

3478

EpiCase

AF:

0.0362

EpiControl

AF:

0.0337

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2018	This variant is associated with the following publications: (PMID: 28008009) -

Abetalipoproteinaemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

T;.;T;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.55

T;T;.;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;.;M;M;M

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.86

N;N;N;N;N

REVEL

Benign

0.026

Sift

Benign

0.12

T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.20, 0.71

.;B;P;P;.

Vest4

0.049, 0.046, 0.044

MutPred

0.28

.;Gain of glycosylation at S127 (P = 0.0253);.;.;.;

MPC

0.22

ClinPred

0.0048

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.050

gMVP

0.29

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