20-34710204-A-T

Variant names:

• chr20-34710204-A-T
• rs1988146807
• NM_021202.3:c.560A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021202.3(TP53INP2):​c.560A>T​(p.Lys187Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TP53INP2 NM_021202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33474272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53INP2	NM_021202.3	c.560A>T	p.Lys187Met	missense_variant	Exon 5 of 5	ENST00000374810.8	NP_067025.1
TP53INP2	NM_001329429.2	c.560A>T	p.Lys187Met	missense_variant	Exon 5 of 5		NP_001316358.1
TP53INP2	NM_001329430.2	c.560A>T	p.Lys187Met	missense_variant	Exon 4 of 4		NP_001316359.1
TP53INP2	NM_001329431.2	c.560A>T	p.Lys187Met	missense_variant	Exon 5 of 5		NP_001316360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53INP2	ENST00000374810.8	c.560A>T	p.Lys187Met	missense_variant	Exon 5 of 5	1	NM_021202.3	ENSP00000363943.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74236

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.560A>T (p.K187M) alteration is located in exon 5 (coding exon 3) of the TP53INP2 gene. This alteration results from a A to T substitution at nucleotide position 560, causing the lysine (K) at amino acid position 187 to be replaced by a methionine (M). 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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	.;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.35
MutPred		0.37		Gain of catalytic residue at K187 (P = 0.0055);Gain of catalytic residue at K187 (P = 0.0055);
MVP		0.35
MPC		2.8
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.27
gMVP		0.37

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: rs1988146807; hg19: chr20-33298008;