Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000370.3(TTPA):c.548T>C(p.Leu183Pro) 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 not provided (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

TTPA
NM_000370.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 8.64

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

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.548T>C	p.Leu183Pro	missense	Exon 3 of 5	NP_000361.1
TTPA	NM_001413418.1		c.665T>C	p.Leu222Pro	missense	Exon 4 of 6	NP_001400347.1
TTPA	NM_001413416.1		c.548T>C	p.Leu183Pro	missense	Exon 3 of 5	NP_001400345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.548T>C	p.Leu183Pro	missense	Exon 3 of 5	ENSP00000260116.4
	TTPA	ENST00000521138.1	TSL:5	n.233-17305T>C		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial isolated deficiency of vitamin E (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.2

PhyloP100

8.6

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.028

Polyphen

0.96

Vest4

0.96

MutPred

0.81

Gain of disorder (P = 0.0592)

MVP

0.90

MPC

0.79

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

0.98

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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NM_000370.3:c.548T>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