8-63064208-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000370.3(TTPA):​c.661C>G​(p.Arg221Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

TTPA
NM_000370.3 missense, splice_region

Scores

11
7
1
Splicing: ADA: 0.7775
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.05
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain CRAL-TRIO (size 165) 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTPANM_000370.3 linkc.661C>G p.Arg221Gly missense_variant, splice_region_variant Exon 4 of 5 ENST00000260116.5 NP_000361.1 P49638

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTPAENST00000260116.5 linkc.661C>G p.Arg221Gly missense_variant, splice_region_variant Exon 4 of 5 1 NM_000370.3 ENSP00000260116.4 P49638
TTPAENST00000521138.1 linkn.233-15605C>G intron_variant Intron 1 of 1 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Uncertain
0.51
T
PROVEAN
Pathogenic
-5.9
D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.86
Loss of catalytic residue at R221 (P = 0.0056);
MVP
0.94
MPC
0.71
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.97
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.78
dbscSNV1_RF
Benign
0.59
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-63976767; API