14-92021739-A-G

Variant names:

• chr14-92021739-A-G
• rs77981249
• NM_004239.4:c.405T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004239.4(TRIP11):​c.405T>C​(p.Ala135Ala) 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:6
• Conservation: PhyloP100: -0.216
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• achondrogenesis type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Laboratory for Molecular Medicine
• TRIP11-related skeletal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP11	NM_004239.4	MANE Select	c.405T>C	p.Ala135Ala	synonymous	Exon 4 of 21	NP_004230.2
	TRIP11	NM_001321851.1		c.402T>C	p.Ala134Ala	synonymous	Exon 4 of 21	NP_001308780.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIP11	ENST00000267622.8	TSL:1 MANE Select	c.405T>C	p.Ala135Ala	synonymous	Exon 4 of 21	ENSP00000267622.4
	TRIP11	ENST00000555516.6	TSL:5	c.-79T>C		5_prime_UTR	Exon 4 of 6	ENSP00000451944.1

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

GnomAD2 exomes AF: 0.0270 AC: 6775 AN: 251354 AF XY: 0.0289

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 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

African (AFR) AF: 0.00233 AC: 78 AN: 33480

American (AMR) AF: 0.00657 AC: 294 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 648 AN: 26134

East Asian (EAS) AF: 0.0915 AC: 3631 AN: 39698

South Asian (SAS) AF: 0.0639 AC: 5514 AN: 86258

European-Finnish (FIN) AF: 0.0341 AC: 1823 AN: 53416

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.0159 AC: 17725 AN: 1111994

Other (OTH) AF: 0.0215 AC: 1296 AN: 60394

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

African (AFR) AF: 0.00334 AC: 139 AN: 41574

American (AMR) AF: 0.0110 AC: 168 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3468

East Asian (EAS) AF: 0.0688 AC: 356 AN: 5174

South Asian (SAS) AF: 0.0818 AC: 395 AN: 4830

European-Finnish (FIN) AF: 0.0313 AC: 332 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1278 AN: 68028

Other (OTH) AF: 0.0165 AC: 35 AN: 2116

Alfa AF: 0.0182 Hom.: 21

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Achondrogenesis, type IA Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 26, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Connective tissue disorder Benign:1

May 11, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.5
DANN	Benign	0.48
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77981249; hg19: chr14-92488083;