Genetic Variant TP53AIP1:p.Ala98Thr (chr11-128935674-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022112.3(TP53AIP1):c.292G>A(p.Ala98Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,434,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. A98P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TP53AIP1
NM_022112.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.555

Publications

0 publications found

Variant links:

Genes affected

TP53AIP1 (HGNC:29984): (tumor protein p53 regulated apoptosis inducing protein 1) This gene is specifically expressed in the thymus, and encodes a protein that is localized to the mitochondrion. The expression of this gene is inducible by p53, and it is thought to play an important role in mediating p53-dependent apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

TP53AIP1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049699962).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022112.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53AIP1	NM_022112.3	MANE Select	c.292G>A	p.Ala98Thr	missense	Exon 4 of 4	NP_071395.2	Q9HCN2-1
TP53AIP1	NM_001195194.1		c.280G>A	p.Ala94Thr	missense	Exon 3 of 3	NP_001182123.1	Q9HCN2-4
TP53AIP1	NM_001251964.2		c.*1818G>A		3_prime_UTR	Exon 2 of 2	NP_001238893.1	Q9HCN2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP53AIP1	ENST00000531399.6	TSL:1 MANE Select	c.292G>A	p.Ala98Thr	missense	Exon 4 of 4	ENSP00000432743.1	Q9HCN2-1
TP53AIP1	ENST00000530777.5	TSL:1	c.280G>A	p.Ala94Thr	missense	Exon 3 of 3	ENSP00000432908.1	Q9HCN2-4
TP53AIP1	ENST00000602346.5	TSL:1	c.*1818G>A		3_prime_UTR	Exon 2 of 2	ENSP00000473353.1	Q9HCN2-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000472

AC:

AN:

211928

AF XY:

0.00000858

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1434216

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

712326

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33266

American (AMR)

AF:

0.00

AC:

AN:

43070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39372

South Asian (SAS)

AF:

0.00

AC:

AN:

83530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106026

Other (OTH)

AF:

0.00

AC:

AN:

59906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.049

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.019

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.28

M_CAP

Benign

0.0019

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.56

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.2

REVEL

Benign

0.0080

Sift

Benign

0.042

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.052

MutPred

0.28

Gain of glycosylation at A98 (P = 0.0171)

MVP

0.048

MPC

0.011

ClinPred

0.030

GERP RS

-1.8

Varity_R

0.032

gMVP

0.0017

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over