rs193921087

Positions:

• chr2-229858949-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001348323.3(TRIP12):​c.850C>A​(p.Pro284Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIP12 NM_001348323.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.56

Genes affected

TRIP12 (HGNC:12306): (thyroid hormone receptor interactor 12) The protein encoded by this gene is an E3 ubiquitin-protein ligase involved in the degradation of the p19ARF/ARF isoform of CDKN2A, a tumor suppressor. The encoded protein also plays a role in the DNA damage response by regulating the stability of USP7, which regulates tumor suppressor p53. [provided by RefSeq, Jan 2017]

TRIP12 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRIP12. . Gene score misZ 4.6402 (greater than the threshold 3.09). Trascript score misZ 6.3495 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, Clark-Baraitser syndrome, complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36766037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIP12	NM_001348323.3	c.850C>A	p.Pro284Thr	missense_variant	4/42	ENST00000675903.1	NP_001335252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIP12	ENST00000675903.1	c.850C>A	p.Pro284Thr	missense_variant	4/42		NM_001348323.3	ENSP00000502713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.69	N;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.61	N;N;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Benign	0.25	T;T;T;.
Polyphen		1.0	D;.;.;.
Vest4		0.54
MutPred		0.34		Gain of phosphorylation at P242 (P = 4e-04);.;.;.;
MVP		0.24
MPC		0.69
ClinPred		0.55	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs193921087; hg19: chr2-230723665; COSMIC: COSV52259104; COSMIC: COSV52259104;