rs1554524061

Positions:

• chr8-63073064-TCC-AAT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000370.3(TTPA):​c.227_229delGGAinsATT​(p.TrpArg76*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTPA NM_000370.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.23

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-63073064-TCC-AAT is Pathogenic according to our data. Variant chr8-63073064-TCC-AAT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTPA	NM_000370.3	c.227_229delGGAinsATT	p.TrpArg76*	stop_gained		ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.227_229delGGAinsATT	p.TrpArg76*	stop_gained		1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.232+12752_232+12754delGGAinsATT		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial isolated deficiency of vitamin E Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 16, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 16, 2024	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551293). This premature translational stop signal has been observed in individual(s) with clinical features of ataxia with isolated vitamin E deficiency (PMID: 18458655). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Trp76_Arg77delinsTyr*) in the TTPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTPA are known to be pathogenic (PMID: 9463307, 26068213). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554524061; hg19: chr8-63985623;