rs4501570

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.677
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
TTPANM_000370.3 linkuse as main transcriptc.663+11T>C intron_variant ENST00000260116.5 NP_000361.1 P49638

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TTPAENST00000260116.5 linkuse as main transcriptc.663+11T>C intron_variant 1 NM_000370.3 ENSP00000260116.4 P49638
TTPAENST00000521138.1 linkuse as main transcriptn.233-15592T>C intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.592
AC:
89798
AN:
151744
Hom.:
28433
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Familial isolated deficiency of vitamin E Benign:4
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 18, 2016Variant 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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4501570; hg19: chr8-63976754; API