chr4-99594865-C-G

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

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

Publications

58 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=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 Benign/Likely_benign. ClinVar VariationId is 129628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 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.891C>G	p.His297Gln	missense	Exon 7 of 18	NP_001373069.1	P55157-1
MTTP	NM_000253.4		c.891C>G	p.His297Gln	missense	Exon 8 of 19	NP_000244.2	P55157-1
MTTP	NM_001300785.2		c.642C>G	p.His214Gln	missense	Exon 7 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.891C>G	p.His297Gln	missense	Exon 7 of 18	ENSP00000265517.5	P55157-1
MTTP	ENST00000457717.6	TSL:5	c.891C>G	p.His297Gln	missense	Exon 8 of 19	ENSP00000400821.1	P55157-1
MTTP	ENST00000511045.6	TSL:2	c.642C>G	p.His214Gln	missense	Exon 7 of 18	ENSP00000427679.2	E9PBP6

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

GnomAD2 exomes

AF:

0.394

AC:

99042

AN:

251152

AF XY:

0.393

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 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

African (AFR)

AF:

0.770

AC:

25763

AN:

33454

American (AMR)

AF:

0.277

AC:

12377

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

15018

AN:

26118

East Asian (EAS)

AF:

0.677

AC:

26867

AN:

39686

South Asian (SAS)

AF:

0.422

AC:

36423

AN:

86230

European-Finnish (FIN)

AF:

0.210

AC:

11196

AN:

53414

Middle Eastern (MID)

AF:

0.514

AC:

2962

AN:

5764

European-Non Finnish (NFE)

AF:

0.356

AC:

395738

AN:

1110910

Other (OTH)

AF:

0.404

AC:

24375

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

18178

36356

54533

72711

90889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12920

25840

38760

51680

64600

<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:

0.469

AC:

71206

AN:

151956

Hom.:

19562

Cov.:

AF XY:

0.462

AC XY:

34332

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.745

AC:

30873

AN:

41458

American (AMR)

AF:

0.363

AC:

5528

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

1993

AN:

3468

East Asian (EAS)

AF:

0.632

AC:

3260

AN:

5156

South Asian (SAS)

AF:

0.414

AC:

1993

AN:

4816

European-Finnish (FIN)

AF:

0.206

AC:

2174

AN:

10568

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.351

AC:

23835

AN:

67942

Other (OTH)

AF:

0.461

AC:

971

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1660

3320

4979

6639

8299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

612

1224

1836

2448

3060

<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:

0.394

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

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 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

5.9

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.088

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.015

MetaRNN

Benign

0.0000022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

-0.41

PrimateAI

Benign

0.23

PROVEAN

Benign

1.0

REVEL

Benign

0.039

Sift

Benign

0.58

Sift4G

Benign

0.52

Polyphen

0.0

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

Mutation Taster

=100/0

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