chr20-34708786-C-T

Variant names:

• chr20-34708786-C-T
• rs777400598
• NM_021202.3:c.47C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_021202.3(TP53INP2):​c.47C>T​(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,609,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TP53INP2 NM_021202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08630937).
• BS2: High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021202.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53INP2	NM_021202.3	MANE Select	c.47C>T	p.Pro16Leu	missense	Exon 3 of 5	NP_067025.1	Q8IXH6
	TP53INP2	NM_001329429.2		c.47C>T	p.Pro16Leu	missense	Exon 3 of 5	NP_001316358.1	Q8IXH6
	TP53INP2	NM_001329430.2		c.47C>T	p.Pro16Leu	missense	Exon 2 of 4	NP_001316359.1	Q8IXH6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53INP2	ENST00000374810.8	TSL:1 MANE Select	c.47C>T	p.Pro16Leu	missense	Exon 3 of 5	ENSP00000363943.3	Q8IXH6
	TP53INP2	ENST00000374809.6	TSL:5	c.47C>T	p.Pro16Leu	missense	Exon 2 of 4	ENSP00000363942.2	Q8IXH6
	TP53INP2	ENST00000894582.1		c.47C>T	p.Pro16Leu	missense	Exon 2 of 4	ENSP00000564641.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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

GnomAD2 exomes AF: 0.00000829 AC: 2 AN: 241166 AF XY: 0.0000153

Gnomad AFR exome AF: 0.000132

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457348 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724532

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110106

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74358

African (AFR) AF: 0.0000482 AC: 2 AN: 41452

American (AMR) AF: 0.000982 AC: 15 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.049
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.049	D
Polyphen		0.14	B
Vest4		0.29
MutPred		0.26		Loss of glycosylation at P16 (P = 0.0176)
MVP		0.067
MPC		0.35
ClinPred		0.28	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.28
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs777400598; hg19: chr20-33296590;