chr8-63061344-CT-C

Variant names:

• chr8-63061344-CT-C
• rs397515377
• NM_000370.3:c.744delA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000370.3(TTPA):​c.744delA​(p.Glu249AsnfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E248E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TTPA NM_000370.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: -1.83
• Publications: 22 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.111 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-63061344-CT-C is Pathogenic according to our data. Variant chr8-63061344-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 9136.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.744delA	p.Glu249AsnfsTer15	frameshift_variant	Exon 5 of 5	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5	c.744delA	p.Glu249AsnfsTer15	frameshift_variant	Exon 5 of 5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1	n.233-12742delA		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251338 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461610 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111878

Other (OTH) AF: 0.0000662 AC: 4 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial isolated deficiency of vitamin E Pathogenic:7 Other:1

Nov 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009136 /PMID: 7719340 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 24, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The TTPA c.744delA (p.Glu249Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent TTPA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000099 (12/121224 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic TTPA variant (0.0020412). The variant has been reported in over 100 patients of Tunisian and Algerian descent who were homozygous for the variant (Euch-Fayache_2014; Hamza_2015). Addtionally, the variant segregated with disease in several consanguineous families, providing strong evidence of pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jan 01, 2015

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is classified as pathogenic in the context of ataxia with vitamin E deficiency. Sources cited for classification include the following: PMID 7719340, 12039660, 9463307 and 15953402. Classification of NM_000370.3(TTPA):c.744delA(aka E249Nfs*15) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -

May 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:2

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu249Asnfs*15) in the TTPA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the TTPA protein. This variant is present in population databases (rs397515377, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ataxia with isolated vitamin E deficiency (PMID: 26068213). ClinVar contains an entry for this variant (Variation ID: 9136). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTPA: PP1:Strong, PM2, PM3, PVS1:Moderate -

Ataxia, Friedreich-like, with isolated vitamin E deficiency Pathogenic:1

Feb 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
Mutation Taster		=20/180	disease causing (ClinVar)

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: rs397515377; hg19: chr8-63973903;