20-34710162-A-T

Variant names:

• chr20-34710162-A-T
• rs1223879477
• NM_021202.3:c.518A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021202.3(TP53INP2):​c.518A>T​(p.Gln173Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000876 in 1,142,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q173R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: TP53INP2 NM_021202.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.52
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.518A>T	p.Gln173Leu	missense	Exon 5 of 5	NP_067025.1	Q8IXH6
	TP53INP2	NM_001329429.2		c.518A>T	p.Gln173Leu	missense	Exon 5 of 5	NP_001316358.1	Q8IXH6
	TP53INP2	NM_001329430.2		c.518A>T	p.Gln173Leu	missense	Exon 4 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.518A>T	p.Gln173Leu	missense	Exon 5 of 5	ENSP00000363943.3	Q8IXH6
	TP53INP2	ENST00000374809.6	TSL:5	c.518A>T	p.Gln173Leu	missense	Exon 4 of 4	ENSP00000363942.2	Q8IXH6
	TP53INP2	ENST00000894582.1		c.518A>T	p.Gln173Leu	missense	Exon 4 of 4	ENSP00000564641.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.76e-7 AC: 1 AN: 1142036 Hom.: 0 Cov.: 33 AF XY: 0.00000182 AC XY: 1 AN XY: 550350

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23896

American (AMR) AF: 0.00 AC: 0 AN: 11816

Ashkenazi Jewish (ASJ) AF: 0.0000619 AC: 1 AN: 16152

East Asian (EAS) AF: 0.00 AC: 0 AN: 26888

South Asian (SAS) AF: 0.00 AC: 0 AN: 36086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 948436

Other (OTH) AF: 0.00 AC: 0 AN: 45770

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.26
MutPred		0.39		Gain of helix (P = 0.0696)
MVP		0.47
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.58
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs1223879477; hg19: chr20-33297966;