Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000370.3(TTPA):c.755T>C(p.Met252Thr) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M252I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TTPA
NM_000370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.33

Publications

0 publications found

Variant links:

Genes affected

TTPA (HGNC:12404): (alpha tocopherol transfer protein) This gene encodes a soluble protein that binds alpha-trocopherol, a form of vitamin E, with high selectivity and affinity. This protein plays an important role in regulating vitamin E levels in the body by transporting vitamin E between membrane vesicles and facilitating the secretion of vitamin E from hepatocytes to circulating lipoproteins. Mutations in this gene cause hereditary vitamin E deficiency (ataxia with vitamin E deficiency, AVED) and retinitis pigmentosa. [provided by RefSeq, Nov 2009]

TTPA Gene-Disease associations (from GenCC):

familial isolated deficiency of vitamin E
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

TTPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a chain Alpha-tocopherol transfer protein (size 277) in uniprot entity TTPA_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000370.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29598328).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000370.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTPA	NM_000370.3	MANE Select	c.755T>C	p.Met252Thr	missense	Exon 5 of 5	NP_000361.1
TTPA	NM_001413418.1		c.872T>C	p.Met291Thr	missense	Exon 6 of 6	NP_001400347.1
TTPA	NM_001413414.1		c.407T>C	p.Met136Thr	missense	Exon 3 of 3	NP_001400343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.755T>C	p.Met252Thr	missense	Exon 5 of 5	ENSP00000260116.4
	TTPA	ENST00000521138.1	TSL:5	n.233-12731T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.62

M_CAP

Benign

0.064

MetaRNN

Benign

0.30

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.6

PhyloP100

8.3

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.012

Polyphen

0.12

Vest4

0.25

MVP

0.91

MPC

0.23

ClinPred

0.90

GERP RS

5.9

Varity_R

0.60

gMVP

0.79

Mutation Taster

=52/48

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000370.3:c.755T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over