chr20-34710207-C-A

Position:

• chr20-34710207-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021202.3(TP53INP2):​c.563C>A​(p.Ala188Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,318,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TP53INP2 NM_021202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.325

Genes affected

TP53INP2 (HGNC:16104): (tumor protein p53 inducible nuclear protein 2) The protein encoded by this gene promotes autophagy and is essential for proper autophagosome formation and processing. In addition, the encoded protein can enhance rDNA transcription by helping in the assembly of the POLR1/RNA polymerase I preinitiation complex. Finally, this protein serves as a transcriptional activator for some genes. [provided by RefSeq, Jul 2016]

NCOA6 (HGNC:15936): (nuclear receptor coactivator 6) The protein encoded by this gene is a transcriptional coactivator that can interact with nuclear hormone receptors to enhance their transcriptional activator functions. This protein has been shown to be involved in the hormone-dependent coactivation of several receptors, including prostanoid, retinoid, vitamin D3, thyroid hormone, and steroid receptors. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054007143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53INP2	NM_021202.3	c.563C>A	p.Ala188Glu	missense_variant	5/5	ENST00000374810.8	NP_067025.1
TP53INP2	NM_001329429.2	c.563C>A	p.Ala188Glu	missense_variant	5/5		NP_001316358.1
TP53INP2	NM_001329430.2	c.563C>A	p.Ala188Glu	missense_variant	4/4		NP_001316359.1
TP53INP2	NM_001329431.2	c.563C>A	p.Ala188Glu	missense_variant	5/5		NP_001316360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53INP2	ENST00000374810.8	c.563C>A	p.Ala188Glu	missense_variant	5/5	1	NM_021202.3	ENSP00000363943	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000152 AC: 2 AN: 1318372 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 652836

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.68e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2024

The c.563C>A (p.A188E) alteration is located in exon 5 (coding exon 3) of the TP53INP2 gene. This alteration results from a C to A substitution at nucleotide position 563, causing the alanine (A) at amino acid position 188 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.034
Sift	Benign	0.086	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.43	B;B
Vest4		0.088
MutPred		0.27		Gain of ubiquitination at K187 (P = 0.0469);Gain of ubiquitination at K187 (P = 0.0469);
MVP		0.17
MPC		1.6
ClinPred		0.083	T
GERP RS		0.82
Varity_R		0.099
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs902395964; hg19: chr20-33298011;