4-99583409-G-C

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.285G>C(p.Gln95His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 1,613,172 control chromosomes in the GnomAD database, including 2,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 196 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2366 hom. )

Consequence

MTTP
NM_001386140.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.112

Publications

21 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=0.0021850765).

BP6

Variant 4-99583409-G-C is Benign according to our data. Variant chr4-99583409-G-C is described in ClinVar as Benign. ClinVar VariationId is 197124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MTTP	NM_001386140.1 link	c.285G>C	p.Gln95His	missense_variant	Exon 3 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.285G>C	p.Gln95His	missense_variant	Exon 4 of 19		NP_000244.2
MTTP	NM_001300785.2 link	c.36G>C	p.Gln12His	missense_variant	Exon 3 of 18		NP_001287714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.285G>C	p.Gln95His	missense_variant	Exon 3 of 18	1	NM_001386140.1	ENSP00000265517.5

Frequencies

GnomAD3 genomes

AF:

0.0489

AC:

7434

AN:

152074

Hom.:

196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.0535

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0383

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0563

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0405

AC:

10068

AN:

248844

AF XY:

0.0413

show subpopulations

Gnomad AFR exome

AF:

0.0483

Gnomad AMR exome

AF:

0.0307

Gnomad ASJ exome

AF:

0.0497

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.0141

Gnomad NFE exome

AF:

0.0542

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0535

AC:

78176

AN:

1460980

Hom.:

2366

Cov.:

AF XY:

0.0528

AC XY:

38383

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.0441

AC:

1476

AN:

33436

American (AMR)

AF:

0.0320

AC:

1430

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0483

AC:

1262

AN:

26102

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39656

South Asian (SAS)

AF:

0.0355

AC:

3059

AN:

86190

European-Finnish (FIN)

AF:

0.0159

AC:

845

AN:

53174

Middle Eastern (MID)

AF:

0.0376

AC:

216

AN:

5752

European-Non Finnish (NFE)

AF:

0.0601

AC:

66855

AN:

1111616

Other (OTH)

AF:

0.0502

AC:

3030

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3714

7428

11142

14856

18570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2498

4996

7494

9992

12490

<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:

0.0489

AC:

7436

AN:

152192

Hom.:

196

Cov.:

AF XY:

0.0474

AC XY:

3528

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0483

AC:

2008

AN:

41550

American (AMR)

AF:

0.0534

AC:

815

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

180

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0381

AC:

184

AN:

4824

European-Finnish (FIN)

AF:

0.0136

AC:

144

AN:

10600

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0563

AC:

3828

AN:

67980

Other (OTH)

AF:

0.0440

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

359

718

1076

1435

1794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0535

Hom.:

166

Bravo

AF:

0.0509

TwinsUK

AF:

0.0666

AC:

247

ALSPAC

AF:

0.0610

AC:

235

ESP6500AA

AF:

0.0511

AC:

225

ESP6500EA

AF:

0.0547

AC:

470

ExAC

AF:

0.0404

AC:

4904

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0561

EpiControl

AF:

0.0618

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 09, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 29, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MTTP c.285G>C (p.Gln95His) results in a non-conservative amino acid change located in the Lipid transport protein, N-terminal domain (IPR001747) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.04 in 248844 control chromosomes in the gnomAD database, including 277 homozygotes. The observed variant frequency is approximately 38- fold the estimated maximal expected allele frequency for a pathogenic variant in MTTP causing Abetalipoproteinaemia (Bassen-Kornzweig Syndrome) phenotype (0.0011), strongly suggesting that the variant is benign. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Abetalipoproteinaemia

Benign:2

Nov 22, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.016

T;.;T;T;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.63

T;T;.;T;T

MetaRNN

Benign

0.0022

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;.;L;L;L

PhyloP100

-0.11

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.61

N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.0010

.;B;B;B;.

Vest4

0.033, 0.018, 0.040

MutPred

0.33

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

MPC

0.23

ClinPred

0.0070

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.43

Mutation Taster

=97/3

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