rs267607138

Positions:

• chr14-92015729-G-A
• chr14-92015729-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004239.4(TRIP11):​c.790C>T​(p.Arg264Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,810 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TRIP11 NM_004239.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.01

Genes affected

TRIP11 (HGNC:12305): (thyroid hormone receptor interactor 11) This gene was identified based on the interaction of its protein product with thyroid hormone receptor beta. This protein is associated with the Golgi apparatus. The N-terminal region of the protein binds Golgi membranes and the C-terminal region binds the minus ends of microtubules; thus, the protein is thought to play a role in assembly and maintenance of the Golgi ribbon structure around the centrosome. Mutations in this gene cause achondrogenesis type IA.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-92015729-G-A is Pathogenic according to our data. Variant chr14-92015729-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 5508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIP11	NM_004239.4	c.790C>T	p.Arg264Ter	stop_gained	6/21	ENST00000267622.8
TRIP11	NM_001321851.1	c.787C>T	p.Arg263Ter	stop_gained	6/21
TRIP11	XR_001750598.3	n.1164C>T		non_coding_transcript_exon_variant	6/15
TRIP11	XR_943560.3	n.1164C>T		non_coding_transcript_exon_variant	6/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIP11	ENST00000267622.8	c.790C>T	p.Arg264Ter	stop_gained	6/21	1	NM_004239.4	P1
TRIP11	ENST00000554357.5	c.25C>T	p.Arg9Ter	stop_gained	1/15	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459810 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726154

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Odontochondrodysplasia 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 21, 2010	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 27, 2019	This variant is interpreted as a Pathogenic for Odontochondrodysplasia, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PVS1, PM3. -

Achondrogenesis, type IA Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5508). This premature translational stop signal has been observed in individual(s) with achondrogenesis and/or odontochondrodysplasia (PMID: 20089971, 30728324). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg264*) in the TRIP11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIP11 are known to be pathogenic (PMID: 20089971, 23956106). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 21, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.88
ClinPred		1.0	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

LitVar

Other links and lift over

dbSNP: rs267607138; hg19: chr14-92482073;