chr2-229778890-AGAGT-A

Variant names:

• chr2-229778890-AGAGT-A
• rs1553591922
• NM_001348323.3:c.5191_5194delACTC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001348323.3(TRIP12):​c.5191_5194delACTC​(p.Thr1731LeufsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIP12 NM_001348323.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.50
• 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-229778890-AGAGT-A is Pathogenic according to our data. Variant chr2-229778890-AGAGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 520615.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.5191_5194delACTC	p.Thr1731LeufsTer39	frameshift	Exon 35 of 42	NP_001335252.1	A0A6Q8PHK0
	TRIP12	NM_001348328.1		c.5194_5197delACTC	p.Thr1732LeufsTer39	frameshift	Exon 35 of 42	NP_001335257.1	A0A6Q8PGG9
	TRIP12	NM_001348329.2		c.5194_5197delACTC	p.Thr1732LeufsTer39	frameshift	Exon 35 of 42	NP_001335258.1	A0A6Q8PGG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP12	ENST00000675903.1	MANE Select	c.5191_5194delACTC	p.Thr1731LeufsTer39	frameshift	Exon 35 of 42	ENSP00000502713.1	A0A6Q8PHK0
	TRIP12	ENST00000389044.8	TSL:1	c.5110_5113delACTC	p.Thr1704LeufsTer39	frameshift	Exon 35 of 42	ENSP00000373696.4	Q14669-3
	TRIP12	ENST00000283943.9	TSL:1	c.4966_4969delACTC	p.Thr1656LeufsTer39	frameshift	Exon 34 of 41	ENSP00000283943.4	Q14669-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553591922; hg19: chr2-230643606;