8-63072990-A-T

Variant names:

• chr8-63072990-A-T
• NM_000370.3:c.303T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000370.3(TTPA):​c.303T>A​(p.His101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTPA NM_000370.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0280

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3	c.303T>A	p.His101Gln	missense_variant	Exon 2 of 5	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.303T>A	p.His101Gln	missense_variant	Exon 2 of 5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.232+12828T>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Benign	0.077	T
Sift4G	Benign	0.33	T
Polyphen		0.041	B
Vest4		0.80
MutPred		0.87		Loss of sheet (P = 0.1398);
MVP		0.72
MPC		0.54
ClinPred		0.84	D
GERP RS		0.78
Varity_R		0.35
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-63985549;