chr8-63064195-A-G

Position:

• chr8-63064195-A-G

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.663+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,586,250 control chromosomes in the GnomAD database, including 203,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (28480 hom., cov: 31)
  • Exomes 𝑓: 0.49 (175485 hom.)
• Consequence: TTPA NM_000370.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.677

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 8-63064195-A-G is Benign according to our data. Variant chr8-63064195-A-G is described in ClinVar as [Benign]. Clinvar id is 363558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-63064195-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTPA	NM_000370.3	c.663+11T>C		intron_variant		ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.663+11T>C		intron_variant		1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.233-15592T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89798 AN: 151744 Hom.: 28433 Cov.: 31

Gnomad AFR AF: 0.817

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.557 AC: 136191 AN: 244296 Hom.: 39827 AF XY: 0.544 AC XY: 71701 AN XY: 131906

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.778

Gnomad SAS exome AF: 0.579

Gnomad FIN exome AF: 0.554

Gnomad NFE exome AF: 0.451

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.486 AC: 697144 AN: 1434388 Hom.: 175485 Cov.: 27 AF XY: 0.487 AC XY: 348033 AN XY: 714858

Gnomad4 AFR exome AF: 0.826

Gnomad4 AMR exome AF: 0.659

Gnomad4 ASJ exome AF: 0.454

Gnomad4 EAS exome AF: 0.767

Gnomad4 SAS exome AF: 0.577

Gnomad4 FIN exome AF: 0.554

Gnomad4 NFE exome AF: 0.447

Gnomad4 OTH exome AF: 0.516

GnomAD4 genome AF: 0.592 AC: 89901 AN: 151862 Hom.: 28480 Cov.: 31 AF XY: 0.597 AC XY: 44312 AN XY: 74186

Gnomad4 AFR AF: 0.817

Gnomad4 AMR AF: 0.602

Gnomad4 ASJ AF: 0.467

Gnomad4 EAS AF: 0.775

Gnomad4 SAS AF: 0.586

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.560

Alfa AF: 0.512 Hom.: 7543

Bravo AF: 0.604

Asia WGS AF: 0.667 AC: 2314 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial isolated deficiency of vitamin E Benign:4

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2016	Variant summary: The TTPA c.663+11T>C variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools via Alamut suggest no significant impact on a normal splicing pattern, however the functional studies confirming these predictions are yet to be conducted. This variant is present in EXAC at a frequency of 0.59 (63955/107728control chrs). The variant of interest is cites as Benign by reputable databases/clinical diagnostic laboratories. Taken together, based on the frequency in the general population, the variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.62
DANN	Benign	0.57

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: rs4501570; hg19: chr8-63976754;