rs199636231

Positions:

chr8-63085844-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BS1_Supporting

The NM_000370.3(TTPA):c.178G>A(p.Asp60Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000732 in 1,536,736 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 1 hom. )

Consequence

TTPA
NM_000370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 5.00

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 links:

TTPA (HGNC:):

TTPA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a chain Alpha-tocopherol transfer protein (size 277) in uniprot entity TTPA_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000370.3

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000765 (1059/1384452) while in subpopulation NFE AF= 0.000922 (993/1077568). AF 95% confidence interval is 0.000874. There are 1 homozygotes in gnomad4_exome. There are 491 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTPA	NM_000370.3 linkuse as main transcript	c.178G>A	p.Asp60Asn	missense_variant	1/5	ENST00000260116.5	NP_000361.1	P49638

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5 linkuse as main transcript	c.178G>A	p.Asp60Asn	missense_variant	1/5	1	NM_000370.3	ENSP00000260116.4		P49638
TTPA	ENST00000521138.1 linkuse as main transcript	n.206G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000385

AC:

AN:

129878

Hom.:

AF XY:

0.000323

AC XY:

AN XY:

71156

show subpopulations

Gnomad AFR exome

AF:

0.000680

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000904

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000865

Gnomad OTH exome

AF:

0.000752

GnomAD4 exome

AF:

0.000765

AC:

1059

AN:

1384452

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

491

AN XY:

683322

show subpopulations

Gnomad4 AFR exome

AF:

0.000225

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000254

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000922

Gnomad4 OTH exome

AF:

0.000989

GnomAD4 genome

AF:

0.000433

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000588

Hom.:

Bravo

AF:

0.000382

ExAC

AF:

0.0000837

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 60 of the TTPA protein (p.Asp60Asn). This variant is present in population databases (rs199636231, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with TTPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 448838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TTPA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 05, 2022	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 19, 2024	PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2017	- -

Familial isolated deficiency of vitamin E

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2024

The c.178G>A (p.D60N) alteration is located in exon 1 (coding exon 1) of the TTPA gene. This alteration results from a G to A substitution at nucleotide position 178, causing the aspartic acid (D) at amino acid position 60 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.47

Sift

Benign

0.33

Sift4G

Benign

0.39

Polyphen

1.0

Vest4

0.37

MVP

0.90

MPC

0.64

ClinPred

0.078

GERP RS

4.3

Varity_R

0.51

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over