8-63073089-C-G

Variant names:

• chr8-63073089-C-G
• rs886040963
• NM_000370.3:c.205-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000370.3(TTPA):​c.205-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTPA NM_000370.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.23
• Publications: 1 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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.9, offset of -23, new splice context is: accatgtatgccatttgtAGaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-63073089-C-G is Pathogenic according to our data. Variant chr8-63073089-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 370407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.205-1G>C		splice_acceptor intron	N/A	NP_000361.1	P49638
	TTPA	NM_001413418.1		c.205-1G>C		splice_acceptor intron	N/A	NP_001400347.1
	TTPA	NM_001413416.1		c.205-1G>C		splice_acceptor 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.205-1G>C		splice_acceptor intron	N/A	ENSP00000260116.4	P49638
	TTPA	ENST00000878696.1		c.205-1G>C		splice_acceptor intron	N/A	ENSP00000548755.1
	TTPA	ENST00000878697.1		c.205-1G>C		splice_acceptor intron	N/A	ENSP00000548756.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248416 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454384 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 723890

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.0000448 AC: 2 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106602

Other (OTH) AF: 0.0000166 AC: 1 AN: 60146

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151884 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74160

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Familial isolated deficiency of vitamin E (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.2
GERP RS		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.94		Position offset: -1

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

Other links and lift over

dbSNP: rs886040963; hg19: chr8-63985648;