8-63064195-A-G

Variant names:

• chr8-63064195-A-G
• rs4501570
• NM_000370.3:c.663+11T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 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 -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 VariationId is 363558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3	c.663+11T>C		intron_variant	Intron 4 of 4	ENST00000260116.5	NP_000361.1

Ensembl

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

GnomAD2 exomes AF: 0.557 AC: 136191 AN: 244296 AF XY: 0.544

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 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

African (AFR) AF: 0.826 AC: 27230 AN: 32948

American (AMR) AF: 0.659 AC: 29146 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 11708 AN: 25770

East Asian (EAS) AF: 0.767 AC: 30228 AN: 39424

South Asian (SAS) AF: 0.577 AC: 49237 AN: 85264

European-Finnish (FIN) AF: 0.554 AC: 29360 AN: 53008

Middle Eastern (MID) AF: 0.520 AC: 2978 AN: 5728

European-Non Finnish (NFE) AF: 0.447 AC: 486583 AN: 1088638

Other (OTH) AF: 0.516 AC: 30674 AN: 59392

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

African (AFR) AF: 0.817 AC: 33877 AN: 41478

American (AMR) AF: 0.602 AC: 9172 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1621 AN: 3470

East Asian (EAS) AF: 0.775 AC: 4001 AN: 5160

South Asian (SAS) AF: 0.586 AC: 2824 AN: 4818

European-Finnish (FIN) AF: 0.552 AC: 5812 AN: 10524

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30973 AN: 67860

Other (OTH) AF: 0.560 AC: 1177 AN: 2100

Alfa AF: 0.515 Hom.: 12287

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Dec 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.62
DANN	Benign	0.57
PhyloP100		-0.68
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: rs4501570; hg19: chr8-63976754;