8-63059765-C-T

Position:

• chr8-63059765-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000370.3(TTPA):​c.*1487G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 151,830 control chromosomes in the GnomAD database, including 22,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22022 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TTPA NM_000370.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.394

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-63059765-C-T is Benign according to our data. Variant chr8-63059765-C-T is described in ClinVar as [Benign]. Clinvar id is 363533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTPA	NM_000370.3	c.*1487G>A		3_prime_UTR_variant	5/5	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116	c.*1487G>A		3_prime_UTR_variant	5/5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.233-11162G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77357 AN: 151712 Hom.: 21983 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.357

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.481

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.510 AC: 77446 AN: 151830 Hom.: 22022 Cov.: 32 AF XY: 0.510 AC XY: 37868 AN XY: 74184

Gnomad4 AFR AF: 0.785

Gnomad4 AMR AF: 0.451

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.481

Gnomad4 FIN AF: 0.465

Gnomad4 NFE AF: 0.386

Gnomad4 OTH AF: 0.488

Alfa AF: 0.470 Hom.: 2236

Bravo AF: 0.516

Asia WGS AF: 0.455 AC: 1571 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial isolated deficiency of vitamin E Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.43

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6472068; hg19: chr8-63972324;