8-63085847-G-T

Variant names:

• chr8-63085847-G-T
• rs397515522
• NM_000370.3:c.175C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000370.3(TTPA):​c.175C>A​(p.Arg59Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R59R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TTPA NM_000370.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.

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.175C>A	p.Arg59Arg	synonymous	Exon 1 of 5	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.175C>A	p.Arg59Arg	synonymous	Exon 1 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.175C>A	p.Arg59Arg	synonymous	Exon 1 of 5	NP_001400345.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.175C>A	p.Arg59Arg	synonymous	Exon 1 of 5	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.175C>A	p.Arg59Arg	synonymous	Exon 1 of 6	ENSP00000548755.1
	TTPA	ENST00000878697.1		c.175C>A	p.Arg59Arg	synonymous	Exon 1 of 4	ENSP00000548756.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384418 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31088

American (AMR) AF: 0.00 AC: 0 AN: 35574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25072

East Asian (EAS) AF: 0.00 AC: 0 AN: 35530

South Asian (SAS) AF: 0.00 AC: 0 AN: 78862

European-Finnish (FIN) AF: 0.0000259 AC: 1 AN: 38578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077574

Other (OTH) AF: 0.00 AC: 0 AN: 57656

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		1.2
PromoterAI		0.0042	Neutral

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: rs397515522; hg19: chr8-63998406;