chr2-229768717-C-A

Position:

• chr2-229768717-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001348323.3(TRIP12):​c.5906G>T​(p.Arg1969Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIP12 NM_001348323.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIP12	NM_001348323.3	c.5906G>T	p.Arg1969Leu	missense_variant, splice_region_variant	41/42	ENST00000675903.1	NP_001335252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIP12	ENST00000675903.1	c.5906G>T	p.Arg1969Leu	missense_variant, splice_region_variant	41/42		NM_001348323.3	ENSP00000502713.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.012	D;D;D;D
Sift4G	Uncertain	0.010	D;T;D;.
Polyphen		0.99	D;.;.;.
Vest4		0.83
MutPred		0.62		Loss of disorder (P = 0.0722);.;.;.;
MVP		0.40
MPC		2.5
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.55
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-230633433;