8-63086020-A-T

Variant names:

• chr8-63086020-A-T
• rs786204758
• NM_000370.3:c.2T>A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000370.3(TTPA):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000783 in 1,276,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: TTPA NM_000370.3 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.00800

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 209 codons. Genomic position: 63064244. Lost 0.747 part of the original CDS.
• PS1: Another start lost variant in NM_000370.3 (TTPA) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-63086020-A-T is Pathogenic according to our data. Variant chr8-63086020-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3	c.2T>A	p.Met1?	start_lost	Exon 1 of 5	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.2T>A	p.Met1?	start_lost	Exon 1 of 5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.30T>A		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.83e-7 AC: 1 AN: 1276684 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 628706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.75e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial isolated deficiency of vitamin E Pathogenic:2

Jan 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the TTPA mRNA. The next in-frame methionine is located at codon 209. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 10360777, 31970222). ClinVar contains an entry for this variant (Variation ID: 371454). This variant disrupts the p.Ala120 amino acid residue in TTPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9463307, 19566498). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.86	T
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		0.020	B
Vest4		0.62
MutPred		0.96		Gain of ubiquitination at M1 (P = 0.0203);
MVP		0.67
ClinPred		0.99	D
GERP RS		-0.16
Varity_R		0.84
gMVP		0.71

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: rs786204758; hg19: chr8-63998579;