rs17029215

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.1151A>C(p.Asp384Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,613,764 control chromosomes in the GnomAD database, including 2,338 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D384N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.070 ( 613 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1725 hom. )

Consequence

MTTP
NM_001386140.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.963

Publications

18 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:

ENSG00000248676 (HGNC:):

ENSG00000248676 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=0.0013110638).

BP6

Variant 4-99600648-A-C is Benign according to our data. Variant chr4-99600648-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 283193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MTTP	NM_001386140.1 link	c.1151A>C	p.Asp384Ala	missense_variant	Exon 9 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.1151A>C	p.Asp384Ala	missense_variant	Exon 10 of 19		NP_000244.2
MTTP	NM_001300785.2 link	c.902A>C	p.Asp301Ala	missense_variant	Exon 9 of 18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.1151A>C	p.Asp384Ala	missense_variant	Exon 9 of 18	1	NM_001386140.1	ENSP00000265517.5

Frequencies

GnomAD3 genomes

AF:

0.0699

AC:

10637

AN:

152098

Hom.:

613

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0481

Gnomad ASJ

AF:

0.0493

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0534

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0650

GnomAD2 exomes

AF:

0.0436

AC:

10959

AN:

251098

AF XY:

0.0417

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.0331

Gnomad ASJ exome

AF:

0.0510

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0547

Gnomad NFE exome

AF:

0.0378

Gnomad OTH exome

AF:

0.0463

GnomAD4 exome

AF:

0.0426

AC:

62288

AN:

1461548

Hom.:

1725

Cov.:

AF XY:

0.0417

AC XY:

30307

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.162

AC:

5412

AN:

33466

American (AMR)

AF:

0.0352

AC:

1575

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0523

AC:

1367

AN:

26120

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39672

South Asian (SAS)

AF:

0.0304

AC:

2624

AN:

86254

European-Finnish (FIN)

AF:

0.0512

AC:

2735

AN:

53412

Middle Eastern (MID)

AF:

0.0470

AC:

271

AN:

5762

European-Non Finnish (NFE)

AF:

0.0408

AC:

45352

AN:

1111772

Other (OTH)

AF:

0.0488

AC:

2949

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

3344

6688

10031

13375

16719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1786

3572

5358

7144

8930

<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:

0.0699

AC:

10647

AN:

152216

Hom.:

613

Cov.:

AF XY:

0.0679

AC XY:

5053

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.153

AC:

6341

AN:

41516

American (AMR)

AF:

0.0481

AC:

734

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0493

AC:

171

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0275

AC:

133

AN:

4828

European-Finnish (FIN)

AF:

0.0534

AC:

566

AN:

10604

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0375

AC:

2554

AN:

68018

Other (OTH)

AF:

0.0643

AC:

136

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

469

938

1408

1877

2346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0499

Hom.:

825

Bravo

AF:

0.0747

TwinsUK

AF:

0.0394

AC:

146

ALSPAC

AF:

0.0400

AC:

154

ESP6500AA

AF:

0.155

AC:

683

ESP6500EA

AF:

0.0393

AC:

338

ExAC

AF:

0.0459

AC:

5567

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0424

EpiControl

AF:

0.0445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Sep 22, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Abetalipoproteinaemia

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 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. -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23475612, 20981092, 15910857, 27884173, 27487388, 30782561) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.17

.;T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.65

T;.;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L;L

PhyloP100

0.96

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.048

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.71

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.025

MPC

0.29

ClinPred

0.0031

GERP RS

0.96

Varity_R

0.10

gMVP

0.22

Mutation Taster

=98/2

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