chr8-63085844-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS1

The NM_000370.3(TTPA):c.178G>A(p.Asp60Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000732 in 1,536,736 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 1 hom. )

Consequence

TTPA
NM_000370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 5.00

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000370.3

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000765 (1059/1384452) while in subpopulation NFE AF = 0.000922 (993/1077568). AF 95% confidence interval is 0.000874. There are 1 homozygotes in GnomAdExome4. There are 491 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTPA	NM_000370.3	MANE Select	c.178G>A	p.Asp60Asn	missense	Exon 1 of 5	NP_000361.1	P49638
TTPA	NM_001413418.1		c.178G>A	p.Asp60Asn	missense	Exon 1 of 6	NP_001400347.1
TTPA	NM_001413416.1		c.178G>A	p.Asp60Asn	missense	Exon 1 of 5	NP_001400345.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTPA	ENST00000260116.5	TSL:1 MANE Select	c.178G>A	p.Asp60Asn	missense	Exon 1 of 5	ENSP00000260116.4	P49638
TTPA	ENST00000878696.1		c.178G>A	p.Asp60Asn	missense	Exon 1 of 6	ENSP00000548755.1
TTPA	ENST00000878697.1		c.178G>A	p.Asp60Asn	missense	Exon 1 of 4	ENSP00000548756.1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000853

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000385

AC:

AN:

129878

AF XY:

0.000323

show subpopulations

Gnomad AFR exome

AF:

0.000680

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000865

Gnomad OTH exome

AF:

0.000752

GnomAD4 exome

AF:

0.000765

AC:

1059

AN:

1384452

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

491

AN XY:

683322

show subpopulations

African (AFR)

AF:

0.000225

AC:

AN:

31080

American (AMR)

AF:

0.00

AC:

AN:

35576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

35524

South Asian (SAS)

AF:

0.0000254

AC:

AN:

78864

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4494

European-Non Finnish (NFE)

AF:

0.000922

AC:

993

AN:

1077568

Other (OTH)

AF:

0.000989

AC:

AN:

57656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

126

188

251

314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000433

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41566

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000853

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000578

Hom.:

Bravo

AF:

0.000382

ExAC

AF:

0.0000837

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Familial isolated deficiency of vitamin E (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.6

PhyloP100

5.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.47

Sift

Benign

0.33

Sift4G

Benign

0.39

Polyphen

1.0

Vest4

0.37

MVP

0.90

MPC

0.64

ClinPred

0.078

GERP RS

4.3

PromoterAI

0.14

Neutral

(source)

Varity_R

0.51

gMVP

0.55

Mutation Taster

=60/40

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over