rs17127837

chr14-91999320-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.4812T>C(p.Asp1604=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00428 in 1,613,904 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (138 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (123 hom.)
• Consequence: TRIP11 NM_004239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0720

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=-0.58).
• BP6: Variant 14-91999320-A-G is Benign according to our data. Variant chr14-91999320-A-G is described in ClinVar as [Benign]. Clinvar id is 314935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.072 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIP11	NM_004239.4	c.4812T>C	p.Asp1604=	synonymous_variant	13/21	ENST00000267622.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIP11	ENST00000267622.8	c.4812T>C	p.Asp1604=	synonymous_variant	13/21	1	NM_004239.4	P1
TRIP11	ENST00000554357.5	c.3960T>C	p.Asp1320=	synonymous_variant	7/15	1
TRIP11	ENST00000557017.1	c.60T>C	p.Asp20=	synonymous_variant, NMD_transcript_variant	1/7	5

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3433 AN: 152148 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00582 AC: 1460 AN: 250894 Hom.: 66 AF XY: 0.00410 AC XY: 556 AN XY: 135602

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00237 AC: 3461 AN: 1461638 Hom.: 123 Cov.: 32 AF XY: 0.00206 AC XY: 1497 AN XY: 727120

Gnomad4 AFR exome AF: 0.0802

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.00561

GnomAD4 genome AF: 0.0226 AC: 3442 AN: 152266 Hom.: 138 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74446

Gnomad4 AFR AF: 0.0784

Gnomad4 AMR AF: 0.00811

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00632 Hom.: 36

Bravo AF: 0.0260

Asia WGS AF: 0.00549 AC: 19 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000296

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 16, 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

Jan 16, 2017

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 22, 2023

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.67
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17127837; hg19: chr14-92465664; COSMIC: COSV50915820;