NM_004881.5:c.664T>C

Variant names:

• chr2-24079596-A-G
• rs1043776561
• NM_004881.5:c.664T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004881.5(TP53I3):​c.664T>C​(p.Trp222Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53I3 NM_004881.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.27
• Publications: 0 publications found

Genes affected

TP53I3 (HGNC:19373): (tumor protein p53 inducible protein 3) The protein encoded by this gene is similar to oxidoreductases, which are enzymes involved in cellular responses to oxidative stresses and irradiation. This gene is induced by the tumor suppressor p53 and is thought to be involved in p53-mediated cell death. It contains a p53 consensus binding site in its promoter region and a downstream pentanucleotide microsatellite sequence. P53 has been shown to transcriptionally activate this gene by interacting with the downstream pentanucleotide microsatellite sequence. The microsatellite is polymorphic, with a varying number of pentanucleotide repeats directly correlated with the extent of transcriptional activation by p53. It has been suggested that the microsatellite polymorphism may be associated with differential susceptibility to cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

FAM228B (HGNC:24736): (family with sequence similarity 228 member B)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004881.5. 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
	TP53I3	NM_004881.5	MANE Select	c.664T>C	p.Trp222Arg	missense	Exon 4 of 5	NP_004872.2
	TP53I3	NM_147184.4		c.664T>C	p.Trp222Arg	missense	Exon 5 of 6	NP_671713.1	Q53FA7-1
	TP53I3	NM_001206802.2		c.619+1223T>C		intron	N/A	NP_001193731.1	Q53FA7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53I3	ENST00000238721.9	TSL:1 MANE Select	c.664T>C	p.Trp222Arg	missense	Exon 4 of 5	ENSP00000238721.4	Q53FA7-1
	TP53I3	ENST00000335934.8	TSL:1	c.664T>C	p.Trp222Arg	missense	Exon 5 of 6	ENSP00000337834.4	Q53FA7-1
	TP53I3	ENST00000407482.5	TSL:1	c.619+1223T>C		intron	N/A	ENSP00000384414.1	Q53FA7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.58		Gain of methylation at W222 (P = 0.0174)
MVP		0.66
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.96
Mutation Taster		=56/44	polymorphism

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: rs1043776561; hg19: chr2-24302466;