Genetic Variant NM_001386140.1:c.2338A>T (chr4-99619094-A-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001386140.1(MTTP):c.2338A>T(p.Asn780Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. N780N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MTTP
NM_001386140.1 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.53

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 4-99619094-A-T is Pathogenic according to our data. Variant chr4-99619094-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14240.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.2338A>T	p.Asn780Tyr	missense_variant	Exon 16 of 18	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.2338A>T	p.Asn780Tyr	missense_variant	Exon 17 of 19		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.2089A>T	p.Asn697Tyr	missense_variant	Exon 16 of 18		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.2338A>T	p.Asn780Tyr	missense_variant	Exon 16 of 18	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Abetalipoproteinaemia

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

.;D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;.;T

M_CAP

Benign

0.077

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.4

.;M;M

PhyloP100

8.5

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.87

MutPred

0.63

Gain of sheet (P = 0.0028);.;.;

MVP

0.89

MPC

0.83

ClinPred

0.96

GERP RS

5.8

Varity_R

0.31

gMVP

0.56

Mutation Taster

=5/95

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over