rs780778324

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_004237.4(TRIP13):​c.77A>G​(p.His26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,444,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TRIP13
NM_004237.4 missense

Scores

1
1
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: -0.936
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-893075-A-G is Pathogenic according to our data. Variant chr5-893075-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 977641.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr5-893075-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRIP13NM_004237.4 linkc.77A>G p.His26Arg missense_variant Exon 1 of 13 ENST00000166345.8 NP_004228.1 Q15645-1
TRIP13NM_001166260.2 linkc.77A>G p.His26Arg missense_variant Exon 1 of 9 NP_001159732.1
TRIP13XM_011514163.2 linkc.77A>G p.His26Arg missense_variant Exon 1 of 14 XP_011512465.1 Q15645-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRIP13ENST00000166345.8 linkc.77A>G p.His26Arg missense_variant Exon 1 of 13 1 NM_004237.4 ENSP00000166345.3 Q15645-1
TRIP13ENST00000512024.5 linkn.192A>G non_coding_transcript_exon_variant Exon 1 of 9 1
TRIP13ENST00000508456.1 linkn.51A>G non_coding_transcript_exon_variant Exon 1 of 3 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000919
AC:
2
AN:
217592
Hom.:
0
AF XY:
0.00000836
AC XY:
1
AN XY:
119632
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000306
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000183
GnomAD4 exome
AF:
0.00000485
AC:
7
AN:
1444434
Hom.:
0
Cov.:
31
AF XY:
0.00000418
AC XY:
3
AN XY:
717804
show subpopulations
Gnomad4 AFR exome
AF:
0.0000302
Gnomad4 AMR exome
AF:
0.0000459
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000511
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000489
Hom.:
0
ExAC
AF:
0.0000167
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 3;C5436599:Oocyte maturation defect 9 Pathogenic:1
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PP3+PM3+PP1+PP4 -

Oocyte maturation defect 9 Pathogenic:1
Apr 10, 2023
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Uncertain:1
Apr 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 26 of the TRIP13 protein (p.His26Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with female infertility (PMID: 32473092, 35812326, 37340965). ClinVar contains an entry for this variant (Variation ID: 977641). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TRIP13 function (PMID: 35812326, 37340965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.099
BayesDel_addAF
Benign
-0.029
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
19
DANN
Benign
0.64
DEOGEN2
Benign
0.10
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.096
N
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.75
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
0.81
L
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.14
N
REVEL
Benign
0.17
Sift
Benign
0.36
T
Sift4G
Benign
0.38
T
Polyphen
0.016
B
Vest4
0.10
MutPred
0.29
Gain of MoRF binding (P = 0.0492);
MVP
0.42
MPC
0.72
ClinPred
0.037
T
GERP RS
-4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.085
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.58
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.58
Position offset: -5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780778324; hg19: chr5-893190; API