8-63078499-G-T

Variant names:

• chr8-63078499-G-T
• rs7842218
• NM_000370.3:c.205-5411C>A

Variant summary

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

The NM_000370.3(TTPA):​c.205-5411C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 152,220 control chromosomes in the GnomAD database, including 646 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 0.068 (646 hom., cov: 33)
• Consequence: TTPA NM_000370.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.969
• Publications: 2 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3	c.205-5411C>A		intron_variant	Intron 1 of 4	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.205-5411C>A		intron_variant	Intron 1 of 4	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.232+7319C>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0677 AC: 10290 AN: 152102 Hom.: 645 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0580

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

GnomAD4 genome AF: 0.0677 AC: 10306 AN: 152220 Hom.: 646 Cov.: 33 AF XY: 0.0677 AC XY: 5038 AN XY: 74420

African (AFR) AF: 0.163 AC: 6769 AN: 41516

American (AMR) AF: 0.0360 AC: 550 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0616 AC: 214 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0298 AC: 144 AN: 4830

European-Finnish (FIN) AF: 0.0594 AC: 629 AN: 10596

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0271 AC: 1842 AN: 68026

Other (OTH) AF: 0.0569 AC: 120 AN: 2108

Alfa AF: 0.0220 Hom.: 18

Bravo AF: 0.0688

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.51
DANN	Benign	0.41
PhyloP100		-0.97
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: rs7842218; hg19: chr8-63991058;