14-92025422-T-C

Position:

• chr14-92025422-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004239.4(TRIP11):​c.202-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000481 in 1,454,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TRIP11 NM_004239.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.71

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]

TRIP11 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018518519 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.3, offset of -31, new splice context is: attacatgttttacttgcAGtct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-92025422-T-C is Pathogenic according to our data. Variant chr14-92025422-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5510.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIP11	NM_004239.4	c.202-2A>G		splice_acceptor_variant, intron_variant		ENST00000267622.8	NP_004230.2
TRIP11	NM_001321851.1	c.199-2A>G		splice_acceptor_variant, intron_variant			NP_001308780.1
TRIP11	XR_001750598.3	n.576-2A>G		splice_acceptor_variant, intron_variant
TRIP11	XR_943560.3	n.576-2A>G		splice_acceptor_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIP11	ENST00000267622.8	c.202-2A>G		splice_acceptor_variant, intron_variant		1	NM_004239.4	ENSP00000267622.4
TRIP11	ENST00000555516.6	c.-282-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000451944.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1454350 Hom.: 0 Cov.: 29 AF XY: 0.00000691 AC XY: 5 AN XY: 723898

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: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Achondrogenesis, type IA Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 16, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the effect of this variant on mRNA splicing is currently unknown. This variant has been observed in individual(s) with clinical features of TRIP11-related conditions (PMID: 20089971). ClinVar contains an entry for this variant (Variation ID: 5510). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 2 of the TRIP11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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	0.33
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: 29
DS_AL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223281; hg19: chr14-92491766;