8-63068288-A-G

Variant names:

• chr8-63068288-A-G
• rs7818611
• NM_000370.3:c.359-2191T>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.359-2191T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,264 control chromosomes in the GnomAD database, including 983 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 0.11 (983 hom., cov: 32)
• Consequence: TTPA NM_000370.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.216
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000370.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	NM_000370.3	MANE Select	c.359-2191T>C		intron	N/A	NP_000361.1
	TTPA	NM_001413418.1		c.475+742T>C		intron	N/A	NP_001400347.1
	TTPA	NM_001413416.1		c.359-2191T>C		intron	N/A	NP_001400345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.359-2191T>C		intron	N/A	ENSP00000260116.4
	TTPA	ENST00000521138.1	TSL:5	n.232+17530T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16192 AN: 152146 Hom.: 984 Cov.: 32

Gnomad AFR AF: 0.0891

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.0950

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0885

Gnomad OTH AF: 0.130

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

GnomAD4 genome AF: 0.106 AC: 16195 AN: 152264 Hom.: 983 Cov.: 32 AF XY: 0.110 AC XY: 8205 AN XY: 74440

African (AFR) AF: 0.0890 AC: 3697 AN: 41552

American (AMR) AF: 0.180 AC: 2759 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 411 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1142 AN: 5180

South Asian (SAS) AF: 0.0954 AC: 461 AN: 4830

European-Finnish (FIN) AF: 0.126 AC: 1338 AN: 10590

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0885 AC: 6021 AN: 68022

Other (OTH) AF: 0.131 AC: 276 AN: 2114

Alfa AF: 0.0925 Hom.: 387

Bravo AF: 0.113

Asia WGS AF: 0.162 AC: 560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.83
PhyloP100		0.22
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: rs7818611; hg19: chr8-63980847;