rs3816873

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.741

Publications

81 publications found

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 Gene-Disease associations (from GenCC):

abetalipoproteinemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia, G2P

MTTP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 14242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
MTTP	NM_001386140.1 link	c.383T>C	p.Ile128Thr	missense_variant	Exon 3 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.383T>C	p.Ile128Thr	missense_variant	Exon 4 of 19		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.134T>C	p.Ile45Thr	missense_variant	Exon 3 of 18		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.383T>C	p.Ile128Thr	missense_variant	Exon 3 of 18	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39787

AN:

151904

Hom.:

5374

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.248

AC:

61707

AN:

248600

AF XY:

0.255

show subpopulations

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 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.:

AF XY:

0.260

AC XY:

189092

AN XY:

726840

show subpopulations

African (AFR)

AF:

0.282

AC:

9422

AN:

33458

American (AMR)

AF:

0.168

AC:

7532

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.398

AC:

10399

AN:

26120

East Asian (EAS)

AF:

0.152

AC:

6029

AN:

39656

South Asian (SAS)

AF:

0.342

AC:

29458

AN:

86228

European-Finnish (FIN)

AF:

0.188

AC:

9999

AN:

53152

Middle Eastern (MID)

AF:

0.352

AC:

2030

AN:

5764

European-Non Finnish (NFE)

AF:

0.255

AC:

283730

AN:

1111638

Other (OTH)

AF:

0.269

AC:

16230

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

14871

29742

44613

59484

74355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9634

19268

28902

38536

48170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.262

AC:

39818

AN:

152022

Hom.:

5382

Cov.:

AF XY:

0.261

AC XY:

19359

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.278

AC:

11525

AN:

41490

American (AMR)

AF:

0.237

AC:

3619

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1385

AN:

3472

East Asian (EAS)

AF:

0.146

AC:

757

AN:

5178

South Asian (SAS)

AF:

0.347

AC:

1672

AN:

4818

European-Finnish (FIN)

AF:

0.190

AC:

2007

AN:

10566

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.260

AC:

17682

AN:

67922

Other (OTH)

AF:

0.298

AC:

627

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1509

3019

4528

6038

7547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

21115

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

LINK: link

Submissions by phenotype

not specified

Benign:3

Jan 05, 2020

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

not provided

Benign:3

Aug 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21438662, 16617174, 16721486, 30782561, 33111339) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Abetalipoproteinaemia

Benign:2

Nov 19, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

METABOLIC SYNDROME, PROTECTION AGAINST

Benign:1

Jan 01, 2006

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Abetalipoproteinaemia;C4552048:Metabolic syndrome X

Benign:1

Mar 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

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

LIST_S2

Benign

0.71

T;T;.;T;T

MetaRNN

Benign

0.00056

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;.;L;L;L

PhyloP100

0.74

PrimateAI

Benign

0.34

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

GERP RS

4.1

Varity_R

0.074

gMVP

0.24

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over