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GeneBe

5-900526-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004237.4(TRIP13):c.421T>C(p.Tyr141His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,602 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y141Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TRIP13
NM_004237.4 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.19
Variant links:
Genes affected
TRIP13 (HGNC:12307): (thyroid hormone receptor interactor 13) This gene encodes a protein that interacts with thyroid hormone receptors, also known as hormone-dependent transcription factors. The gene product interacts specifically with the ligand binding domain. This gene is one of several that may play a role in early-stage non-small cell lung cancer. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRIP13NM_004237.4 linkuse as main transcriptc.421T>C p.Tyr141His missense_variant 4/13 ENST00000166345.8
TRIP13NM_001166260.2 linkuse as main transcriptc.421T>C p.Tyr141His missense_variant 4/9
TRIP13XM_011514163.2 linkuse as main transcriptc.421T>C p.Tyr141His missense_variant 4/14
TRIP13XM_047417879.1 linkuse as main transcriptc.-39T>C 5_prime_UTR_variant 4/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRIP13ENST00000166345.8 linkuse as main transcriptc.421T>C p.Tyr141His missense_variant 4/131 NM_004237.4 P1Q15645-1
TRIP13ENST00000512024.5 linkuse as main transcriptn.536T>C non_coding_transcript_exon_variant 4/91
TRIP13ENST00000513435.1 linkuse as main transcriptc.409T>C p.Tyr137His missense_variant 4/85

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459602
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726098
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 03, 2022The c.421T>C (p.Y141H) alteration is located in exon 4 (coding exon 4) of the TRIP13 gene. This alteration results from a T to C substitution at nucleotide position 421, causing the tyrosine (Y) at amino acid position 141 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
Cadd
Uncertain
25
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.33
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Pathogenic
3.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.79
MutPred
0.82
Gain of disorder (P = 0.0512);
MVP
0.88
MPC
1.8
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.84

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-900641; API