Genetic Variant TTPA:p.Arg59Gly (chr8-63085847-G-C) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000370.3(TTPA):c.175C>G(p.Arg59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TTPA
NM_000370.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.23

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000370.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-63085847-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65589.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3 link	c.175C>G	p.Arg59Gly	missense_variant	Exon 1 of 5	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5 link	c.175C>G	p.Arg59Gly	missense_variant	Exon 1 of 5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1 link	n.203C>G		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1384418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31088

American (AMR)

AF:

0.00

AC:

AN:

35574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25072

East Asian (EAS)

AF:

0.00

AC:

AN:

35530

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4484

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077574

Other (OTH)

AF:

0.00

AC:

AN:

57656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

Eigen

Benign

0.14

Eigen_PC

Benign

-0.043

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

4.0

PhyloP100

1.2

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Vest4

0.57

ClinPred

1.0

GERP RS

1.2

PromoterAI

0.043

Neutral

(source)

Varity_R

0.95

gMVP

0.85

Mutation Taster

=33/67

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over