rs143524436

Positions:

• chr14-92005842-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004239.4(TRIP11):​c.2134G>A​(p.Glu712Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00886 in 1,614,040 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (89 hom.)
• Consequence: TRIP11 NM_004239.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.85

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049014688).
• BP6: Variant 14-92005842-C-T is Benign according to our data. Variant chr14-92005842-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 314964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-92005842-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00802 (1221/152308) while in subpopulation NFE AF= 0.0103 (700/68026). AF 95% confidence interval is 0.00966. There are 10 homozygotes in gnomad4. There are 643 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIP11	NM_004239.4	c.2134G>A	p.Glu712Lys	missense_variant	11/21	ENST00000267622.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIP11	ENST00000267622.8	c.2134G>A	p.Glu712Lys	missense_variant	11/21	1	NM_004239.4	P1
TRIP11	ENST00000554357.5	c.1282G>A	p.Glu428Lys	missense_variant	5/15	1

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1222 AN: 152190 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00764 AC: 1915 AN: 250718 Hom.: 6 AF XY: 0.00765 AC XY: 1037 AN XY: 135578

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.00905

Gnomad OTH exome AF: 0.00964

GnomAD4 exome AF: 0.00894 AC: 13073 AN: 1461732 Hom.: 89 Cov.: 32 AF XY: 0.00879 AC XY: 6392 AN XY: 727164

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00299

Gnomad4 FIN exome AF: 0.0308

Gnomad4 NFE exome AF: 0.00938

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.00802 AC: 1221 AN: 152308 Hom.: 10 Cov.: 33 AF XY: 0.00863 AC XY: 643 AN XY: 74490

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00858 Hom.: 7

Bravo AF: 0.00592

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00965 AC: 83

ExAC AF: 0.00741 AC: 899

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00976

EpiControl AF: 0.0100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TRIP11: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Achondrogenesis, type IA Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Achondrogenesis, type IA;C5542277:Odontochondrodysplasia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2021

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.026	D
Polyphen		0.98	D
Vest4		0.19
MVP		0.45
MPC		0.24
ClinPred		0.020	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.34

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: rs143524436; hg19: chr14-92472186; COSMIC: COSV99970496;