2-229767605-T-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001348323.3(TRIP12):​c.6153A>T​(p.Glu2051Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TRIP12
NM_001348323.3 missense

Scores

4
15

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.426

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13957751).
BP6
Variant 2-229767605-T-A is Benign according to our data. Variant chr2-229767605-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3058700.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRIP12NM_001348323.3 linkc.6153A>T p.Glu2051Asp missense_variant Exon 42 of 42 ENST00000675903.1 NP_001335252.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRIP12ENST00000675903.1 linkc.6153A>T p.Glu2051Asp missense_variant Exon 42 of 42 NM_001348323.3 ENSP00000502713.1 A0A6Q8PHK0

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000120
AC:
3
AN:
251024
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461596
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727094
show subpopulations
African (AFR)
AF:
0.000120
AC:
4
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44680
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86160
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111908
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152238
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74380
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41468
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

TRIP12-related disorder Benign:1
Sep 08, 2022
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
14
DANN
Uncertain
1.0
DEOGEN2
Benign
0.066
T;.;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.42
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
L;.;.
PhyloP100
0.43
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.73
N;N;N
REVEL
Benign
0.096
Sift
Benign
0.33
T;T;T
Sift4G
Benign
0.33
T;T;T
Polyphen
0.0010
B;.;.
Vest4
0.093
MutPred
0.53
Gain of ubiquitination at K1977 (P = 0.0898);.;.;
MVP
0.22
MPC
2.0
ClinPred
0.12
T
GERP RS
-0.83
Varity_R
0.092
gMVP
0.83
Mutation Taster
=82/18
polymorphism

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

Other links and lift over

dbSNP: rs779710378; hg19: chr2-230632321; API