rs77981249

Positions:

• chr14-92021739-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004239.4(TRIP11):​c.405T>C​(p.Ala135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,614,178 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (53 hom., cov: 32)
  • Exomes 𝑓: 0.021 (677 hom.)
• Consequence: TRIP11 NM_004239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.216

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-92021739-A-G is Benign according to our data. Variant chr14-92021739-A-G is described in ClinVar as [Benign]. Clinvar id is 314977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.216 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIP11	NM_004239.4	c.405T>C	p.Ala135=	synonymous_variant	4/21	ENST00000267622.8
TRIP11	NM_001321851.1	c.402T>C	p.Ala134=	synonymous_variant	4/21
TRIP11	XR_001750598.3	n.779T>C		non_coding_transcript_exon_variant	4/15
TRIP11	XR_943560.3	n.779T>C		non_coding_transcript_exon_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIP11	ENST00000267622.8	c.405T>C	p.Ala135=	synonymous_variant	4/21	1	NM_004239.4	P1
TRIP11	ENST00000555516.6	c.-79T>C		5_prime_UTR_variant	4/6	5

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2834 AN: 152194 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00335

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.0811

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0270 AC: 6775 AN: 251354 Hom.: 198 AF XY: 0.0289 AC XY: 3929 AN XY: 135842

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.0626

Gnomad SAS exome AF: 0.0667

Gnomad FIN exome AF: 0.0347

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0213 AC: 31070 AN: 1461866 Hom.: 677 Cov.: 32 AF XY: 0.0225 AC XY: 16399 AN XY: 727232

Gnomad4 AFR exome AF: 0.00233

Gnomad4 AMR exome AF: 0.00657

Gnomad4 ASJ exome AF: 0.0248

Gnomad4 EAS exome AF: 0.0915

Gnomad4 SAS exome AF: 0.0639

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0215

GnomAD4 genome AF: 0.0186 AC: 2834 AN: 152312 Hom.: 53 Cov.: 32 AF XY: 0.0202 AC XY: 1507 AN XY: 74476

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.0688

Gnomad4 SAS AF: 0.0818

Gnomad4 FIN AF: 0.0313

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.0178 Hom.: 16

Bravo AF: 0.0146

Asia WGS AF: 0.0680 AC: 236 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0176

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 26, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.48

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: rs77981249; hg19: chr14-92488083;