rs4587328

Positions:

• chr8-63060159-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.*1093G>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 0.591 in 152,090 control chromosomes in the GnomAD database, including 28,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28444 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: -0.471

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-63060159-C-T is Benign according to our data. Variant chr8-63060159-C-T is described in ClinVar as [Benign]. Clinvar id is 363543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTPA	NM_000370.3	c.*1093G>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.*1093G>A		3_prime_UTR_variant	5/5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.233-11556G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89829 AN: 151974 Hom.: 28398 Cov.: 32

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.554

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: 0.591 AC: 89929 AN: 152090 Hom.: 28444 Cov.: 32 AF XY: 0.597 AC XY: 44360 AN XY: 74354

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.602

Gnomad4 ASJ AF: 0.467

Gnomad4 EAS AF: 0.774

Gnomad4 SAS AF: 0.585

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.559

Alfa AF: 0.412 Hom.: 1182

Bravo AF: 0.603

Asia WGS AF: 0.669 AC: 2323 AN: 3476

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 12, 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	-0.90
CADD	Benign	1.6
DANN	Benign	0.46

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

LitVar

Other links and lift over

dbSNP: rs4587328; hg19: chr8-63972718;