4-99597126-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001386140.1(MTTP):c.969T>C(p.Ala323Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,613,882 control chromosomes in the GnomAD database, including 11,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 998 hom., cov: 32)

Exomes 𝑓: 0.11 ( 10290 hom. )

Consequence

MTTP
NM_001386140.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.07

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 4-99597126-T-C is Benign according to our data. Variant chr4-99597126-T-C is described in ClinVar as Benign. ClinVar VariationId is 129629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_001386140.1 link	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 8 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 9 of 19		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.720T>C	p.Ala240Ala	synonymous_variant	Exon 8 of 18		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.969T>C	p.Ala323Ala	synonymous_variant	Exon 8 of 18	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15852

AN:

152072

Hom.:

997

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.341

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.262

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0669

Gnomad FIN

AF:

0.0548

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.121

GnomAD2 exomes

AF:

0.0971

AC:

24389

AN:

251068

AF XY:

0.0983

show subpopulations

Gnomad AFR exome

AF:

0.0845

Gnomad AMR exome

AF:

0.0704

Gnomad ASJ exome

AF:

0.279

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0532

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.129

GnomAD4 exome

AF:

0.112

AC:

164426

AN:

1461692

Hom.:

10290

Cov.:

AF XY:

0.112

AC XY:

81465

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.0864

AC:

2892

AN:

33468

American (AMR)

AF:

0.0743

AC:

3324

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6985

AN:

26128

East Asian (EAS)

AF:

0.000328

AC:

AN:

39694

South Asian (SAS)

AF:

0.0772

AC:

6661

AN:

86254

European-Finnish (FIN)

AF:

0.0556

AC:

2968

AN:

53410

Middle Eastern (MID)

AF:

0.185

AC:

1065

AN:

5766

European-Non Finnish (NFE)

AF:

0.120

AC:

133331

AN:

1111864

Other (OTH)

AF:

0.119

AC:

7187

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

8392

16784

25176

33568

41960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4796

9592

14388

19184

23980

<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:

0.104

AC:

15872

AN:

152190

Hom.:

998

Cov.:

AF XY:

0.102

AC XY:

7626

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0864

AC:

3589

AN:

41530

American (AMR)

AF:

0.107

AC:

1639

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

908

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0670

AC:

323

AN:

4824

European-Finnish (FIN)

AF:

0.0548

AC:

581

AN:

10608

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8207

AN:

67982

Other (OTH)

AF:

0.119

AC:

252

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

718

1436

2153

2871

3589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

368

552

736

920

<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:

0.125

Hom.:

1020

Bravo

AF:

0.107

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

EpiCase

AF:

0.128

EpiControl

AF:

0.128

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Apr 12, 2020

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

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. -

Abetalipoproteinaemia

Benign:2

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. -

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.15

(source)

DANN

Benign

0.47

PhyloP100

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over