chr8-63072935-C-G

Variant names:

• chr8-63072935-C-G
• rs143010236
• NM_000370.3:c.358G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000370.3(TTPA):​c.358G>C​(p.Ala120Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A120T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTPA NM_000370.3 missense, splice_region
• Scores: Splicing: ADA: 0.9990
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.55
• Publications: 13 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 7 ACMG points.

• PM1: In a chain Alpha-tocopherol transfer protein (size 277) in uniprot entity TTPA_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000370.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-63072935-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	NM_000370.3	MANE Select	c.358G>C	p.Ala120Pro	missense splice_region	Exon 2 of 5	NP_000361.1
	TTPA	NM_001413418.1		c.358G>C	p.Glu120Gln	missense splice_region	Exon 2 of 6	NP_001400347.1
	TTPA	NM_001413416.1		c.358G>C	p.Ala120Pro	missense splice_region	Exon 2 of 5	NP_001400345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTPA	ENST00000260116.5	TSL:1 MANE Select	c.358G>C	p.Ala120Pro	missense splice_region	Exon 2 of 5	ENSP00000260116.4
	TTPA	ENST00000521138.1	TSL:5	n.232+12883G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.012	D
Sift4G	Benign	0.19	T
Polyphen		0.51	P
Vest4		0.56
MutPred		0.75		Loss of catalytic residue at A120 (P = 0.0409)
MVP		0.96
MPC		0.47
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.87
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 0

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

Other links and lift over

dbSNP: rs143010236; hg19: chr8-63985494; COSMIC: COSV99478558;