NM_000370.3:c.359-1_360delGCAinsCCC

Variant names:

• chr8-63066096-TGC-GGG
• NM_000370.3:c.359-1_360delGCAinsCCC
• TTPA p.121

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000370.3(TTPA):​c.359-1_360delGCAinsCCC​(p.121) variant causes a splice acceptor, splice region, synonymous, intron change. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 0)
• Consequence: TTPA NM_000370.3 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.88
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000370.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	NM_000370.3	MANE Select	c.359-1_360delGCAinsCCC	p.121	splice_acceptor splice_region synonymous intron	N/A	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.476-1_477delGCAinsCCC	p.160	splice_acceptor splice_region synonymous intron	N/A	NP_001400347.1
	TTPA	NM_001413416.1		c.359-1_360delGCAinsCCC	p.121	splice_acceptor splice_region synonymous intron	N/A	NP_001400345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.359-1_360delGCAinsCCC	p.121	splice_acceptor splice_region synonymous intron	N/A	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.476-1_477delGCAinsCCC	p.160	splice_acceptor splice_region synonymous intron	N/A	ENSP00000548755.1
	TTPA	ENST00000878697.1		c.359-1_360delGCAinsCCC	p.121	splice_acceptor splice_region synonymous intron	N/A	ENSP00000548756.1

Frequencies

GnomAD3 genomes Cov.: 0

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

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-63978655;