Genetic Variant NM_001348323.3:c.5009G>A (chr2-229785842-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001348323.3(TRIP12):c.5009G>A(p.Arg1670Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRIP12
NM_001348323.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.51

Publications

0 publications found

Variant links:

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

TRIP12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001348323.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

PP5

Variant 2-229785842-C-T is Pathogenic according to our data. Variant chr2-229785842-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446138.Status of the report is no_assertion_criteria_provided, 0 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRIP12	NM_001348323.3	MANE Select	c.5009G>A	p.Arg1670Gln	missense	Exon 34 of 42	NP_001335252.1
TRIP12	NM_001348328.1		c.5012G>A	p.Arg1671Gln	missense	Exon 34 of 42	NP_001335257.1
TRIP12	NM_001348329.2		c.5012G>A	p.Arg1671Gln	missense	Exon 34 of 42	NP_001335258.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRIP12	ENST00000675903.1	MANE Select	c.5009G>A	p.Arg1670Gln	missense	Exon 34 of 42	ENSP00000502713.1
TRIP12	ENST00000389044.8	TSL:1	c.4928G>A	p.Arg1643Gln	missense	Exon 34 of 42	ENSP00000373696.4
TRIP12	ENST00000283943.9	TSL:1	c.4784G>A	p.Arg1595Gln	missense	Exon 33 of 41	ENSP00000283943.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461072

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111706

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Clark-Baraitser syndrome

Pathogenic:1

Apr 15, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.0093

MutationAssessor

Pathogenic

3.9

PhyloP100

7.5

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.99

MutPred

0.56

Loss of MoRF binding (P = 0.0473)

MVP

0.92

MPC

2.4

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

1.0

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

1.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over