chr8-63059884-G-C

Variant names:

• chr8-63059884-G-C
• rs553853197
• NM_000370.3:c.*1368C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_000370.3(TTPA):​c.*1368C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 152,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000099 (0 hom., cov: 32)
• Consequence: TTPA NM_000370.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.358
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000986 (15/152060) while in subpopulation EAS AF = 0.0029 (15/5170). AF 95% confidence interval is 0.00179. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*1368C>G		3_prime_UTR	Exon 5 of 5	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.*1368C>G		3_prime_UTR	Exon 6 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.*2107C>G		3_prime_UTR	Exon 5 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.*1368C>G		3_prime_UTR	Exon 5 of 5	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.*1368C>G		3_prime_UTR	Exon 6 of 6	ENSP00000548755.1
	TTPA	ENST00000878694.1		c.*1368C>G		3_prime_UTR	Exon 5 of 5	ENSP00000548753.1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151942 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial isolated deficiency of vitamin E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		0.36

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: rs553853197; hg19: chr8-63972443;