20-34709371-G-C

Variant names:

• chr20-34709371-G-C
• rs751858449
• NM_021202.3:c.260G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021202.3(TP53INP2):​c.260G>C​(p.Gly87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,510 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TP53INP2 NM_021202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16197905).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53INP2	NM_021202.3	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 5	ENST00000374810.8	NP_067025.1
TP53INP2	NM_001329429.2	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 5		NP_001316358.1
TP53INP2	NM_001329430.2	c.260G>C	p.Gly87Ala	missense_variant	Exon 3 of 4		NP_001316359.1
TP53INP2	NM_001329431.2	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 5		NP_001316360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53INP2	ENST00000374810.8	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 5	1	NM_021202.3	ENSP00000363943.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 248096 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461510 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.260G>C (p.G87A) alteration is located in exon 4 (coding exon 2) of the TP53INP2 gene. This alteration results from a G to C substitution at nucleotide position 260, causing the glycine (G) at amino acid position 87 to be replaced by an alanine (A). 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	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.76	N;N;D
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;D
Sift4G	Benign	1.0	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.42
MutPred		0.15		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.38
MPC		0.89
ClinPred		0.69	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751858449; hg19: chr20-33297175;