5-893075-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TRIP13 NM_004237.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.936

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-893075-A-G is Pathogenic according to our data. Variant chr5-893075-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 977641.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-893075-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIP13	NM_004237.4	c.77A>G	p.His26Arg	missense_variant	1/13	ENST00000166345.8
TRIP13	NM_001166260.2	c.77A>G	p.His26Arg	missense_variant	1/9
TRIP13	XM_011514163.2	c.77A>G	p.His26Arg	missense_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIP13	ENST00000166345.8	c.77A>G	p.His26Arg	missense_variant	1/13	1	NM_004237.4	P1
TRIP13	ENST00000512024.5	n.192A>G		non_coding_transcript_exon_variant	1/9	1
TRIP13	ENST00000508456.1	n.51A>G		non_coding_transcript_exon_variant	1/3	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

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

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: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oocyte maturation defect 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 10, 2023

- -

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
MutationTaster	Benign	1.0	N
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

Other links and lift over

dbSNP: rs780778324; hg19: chr5-893190;