Genetic Variant MTTP:p.Ser590Ile (chr4-99608977-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001386140.1(MTTP):c.1769G>T(p.Ser590Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S590N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MTTP
NM_001386140.1 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 7.16

Publications

14 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: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-99608977-G-T is Pathogenic according to our data. Variant chr4-99608977-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14241.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_001386140.1 link	c.1769G>T	p.Ser590Ile	missense_variant, splice_region_variant	Exon 12 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.1769G>T	p.Ser590Ile	missense_variant, splice_region_variant	Exon 13 of 19		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.1520G>T	p.Ser507Ile	missense_variant, splice_region_variant	Exon 12 of 18		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.1769G>T	p.Ser590Ile	missense_variant, splice_region_variant	Exon 12 of 18	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1456558

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724896

African (AFR)

AF:

0.00

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107244

Other (OTH)

AF:

0.00

AC:

AN:

60218

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Abetalipoproteinaemia

Pathogenic:1Other:1

Feb 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;D;D

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;D

M_CAP

Benign

0.033

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

2.9

.;M;M

PhyloP100

7.2

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.027

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.86

MutPred

0.65

Loss of glycosylation at P615 (P = 0.0617);.;.;

MVP

0.92

MPC

0.82

ClinPred

0.99

GERP RS

5.0

Varity_R

0.56

gMVP

0.68

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.72

Position offset: 0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over