rs200318321

Variant names:

• chr20-34709324-G-C
• rs200318321
• NM_021202.3:c.213G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_021202.3(TP53INP2):​c.213G>C​(p.Trp71Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: TP53INP2 NM_021202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• BS2: High AC in GnomAd4 at 12 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.213G>C	p.Trp71Cys	missense	Exon 4 of 5	NP_067025.1	Q8IXH6
	TP53INP2	NM_001329429.2		c.213G>C	p.Trp71Cys	missense	Exon 4 of 5	NP_001316358.1	Q8IXH6
	TP53INP2	NM_001329430.2		c.213G>C	p.Trp71Cys	missense	Exon 3 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.213G>C	p.Trp71Cys	missense	Exon 4 of 5	ENSP00000363943.3	Q8IXH6
	TP53INP2	ENST00000374809.6	TSL:5	c.213G>C	p.Trp71Cys	missense	Exon 3 of 4	ENSP00000363942.2	Q8IXH6
	TP53INP2	ENST00000894582.1		c.213G>C	p.Trp71Cys	missense	Exon 3 of 4	ENSP00000564641.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 244594 AF XY: 0.0000224

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: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1461154 Hom.: 0 Cov.: 36 AF XY: 0.000157 AC XY: 114 AN XY: 726914

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000202 AC: 225 AN: 1111772

Other (OTH) AF: 0.0000497 AC: 3 AN: 60346

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74286

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67980

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

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.44		Gain of glycosylation at S70 (P = 0.0235)
MVP		0.83
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.78
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200318321; hg19: chr20-33297128;