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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

MTTP links:

ENSG00000248676 (HGNC:54189):

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386140.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTTP	NM_001386140.1	MANE Select	c.1151A>C	p.Asp384Ala	missense	Exon 9 of 18	NP_001373069.1	P55157-1
MTTP	NM_000253.4		c.1151A>C	p.Asp384Ala	missense	Exon 10 of 19	NP_000244.2	P55157-1
MTTP	NM_001300785.2		c.902A>C	p.Asp301Ala	missense	Exon 9 of 18	NP_001287714.2	E9PBP6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTTP	ENST00000265517.10	TSL:1 MANE Select	c.1151A>C	p.Asp384Ala	missense	Exon 9 of 18	ENSP00000265517.5	P55157-1
MTTP	ENST00000457717.6	TSL:5	c.1151A>C	p.Asp384Ala	missense	Exon 10 of 19	ENSP00000400821.1	P55157-1
MTTP	ENST00000511045.6	TSL:2	c.902A>C	p.Asp301Ala	missense	Exon 9 of 18	ENSP00000427679.2	E9PBP6

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Abetalipoproteinaemia (3)

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.96

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.6

REVEL

Benign

0.048

Sift

Benign

0.39

Sift4G

Benign

0.71

Polyphen

0.0020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over