rs1553612358

Variant names:

• chr2-229795178-C-A
• rs1553612358
• NM_001348323.3:c.3968+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-229795178-C-A
• chr2-229795178-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_001348323.3(TRIP12):​c.3968+1G>T variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001582096: Disruption of this splice site has been observed in individual(s) with clinical features of TRIP12-related conditions (PMID:28251352).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIP12 NM_001348323.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Clark-Baraitser syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024500322 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of 42, new splice context is: ttgGTactt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001582096: Disruption of this splice site has been observed in individual(s) with clinical features of TRIP12-related conditions (PMID: 28251352).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-229795178-C-A is Pathogenic according to our data. Variant chr2-229795178-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1070789.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348323.3. 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
	TRIP12	NM_001348323.3	MANE Select	c.3968+1G>T		splice_donor intron	N/A	NP_001335252.1	A0A6Q8PHK0
	TRIP12	NM_001348328.1		c.3971+1G>T		splice_donor intron	N/A	NP_001335257.1	A0A6Q8PGG9
	TRIP12	NM_001348329.2		c.3971+1G>T		splice_donor intron	N/A	NP_001335258.1	A0A6Q8PGG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP12	ENST00000675903.1	MANE Select	c.3968+1G>T		splice_donor intron	N/A	ENSP00000502713.1	A0A6Q8PHK0
	TRIP12	ENST00000389044.8	TSL:1	c.3887+1G>T		splice_donor intron	N/A	ENSP00000373696.4	Q14669-3
	TRIP12	ENST00000283943.9	TSL:1	c.3743+1G>T		splice_donor intron	N/A	ENSP00000283943.4	Q14669-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.4
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: 39
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553612358; hg19: chr2-230659894;