NM_000370.3:c.359-2372T>C

Variant names:

• chr8-63068469-A-G
• rs7818905
• NM_000370.3:c.359-2372T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000370.3(TTPA):​c.359-2372T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 152,164 control chromosomes in the GnomAD database, including 52,361 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (52361 hom., cov: 31)
• Consequence: TTPA NM_000370.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 3 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3	c.359-2372T>C		intron_variant	Intron 2 of 4	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.359-2372T>C		intron_variant	Intron 2 of 4	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.232+17349T>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125291 AN: 152046 Hom.: 52294 Cov.: 31

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.977

Gnomad SAS AF: 0.884

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.814

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.824 AC: 125417 AN: 152164 Hom.: 52361 Cov.: 31 AF XY: 0.830 AC XY: 61746 AN XY: 74390

African (AFR) AF: 0.949 AC: 39426 AN: 41538

American (AMR) AF: 0.831 AC: 12704 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2616 AN: 3470

East Asian (EAS) AF: 0.977 AC: 5048 AN: 5166

South Asian (SAS) AF: 0.885 AC: 4269 AN: 4826

European-Finnish (FIN) AF: 0.810 AC: 8585 AN: 10594

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.738 AC: 50156 AN: 67976

Other (OTH) AF: 0.817 AC: 1723 AN: 2110

Alfa AF: 0.792 Hom.: 16237

Bravo AF: 0.831

Asia WGS AF: 0.923 AC: 3212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.6
DANN	Benign	0.70
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7818905; hg19: chr8-63981028;