dbSNP rs786204758: TTPA:p.Met1? (chr8-63086020-A-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_000370.3(TTPA):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000783 in 1,276,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

TTPA
NM_000370.3 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00800

Publications

0 publications found

Variant links:

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)

TTPA links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 65 pathogenic variants. Next in-frame start position is after 209 codons. Genomic position: 63064244. Lost 0.747 part of the original CDS.

PS1

Another start lost variant in NM_000370.3 (TTPA) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTPA	NM_000370.3 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 5	ENST00000260116.5	NP_000361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTPA	ENST00000260116.5 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 5	1	NM_000370.3	ENSP00000260116.4
TTPA	ENST00000521138.1 link	n.30T>G		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.83e-7

AC:

AN:

1276686

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

628708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26012

American (AMR)

AF:

0.00

AC:

AN:

23112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21604

East Asian (EAS)

AF:

0.00

AC:

AN:

27494

South Asian (SAS)

AF:

0.00

AC:

AN:

65204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3672

European-Non Finnish (NFE)

AF:

9.75e-7

AC:

AN:

1025536

Other (OTH)

AF:

0.00

AC:

AN:

52050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.34

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.86

PhyloP100

-0.0080

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Vest4

0.42

ClinPred

0.99

GERP RS

-0.16

PromoterAI

0.0066

Neutral

(source)

Varity_R

0.88

gMVP

0.70

Mutation Taster

=48/152

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over