rs139539448

Variant names:

• chr14-92005874-T-C
• rs139539448
• NM_004239.4:c.2102A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004239.4(TRIP11):​c.2102A>G​(p.Asn701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,040 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: TRIP11 NM_004239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.634

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058752716).
• BP6: Variant 14-92005874-T-C is Benign according to our data. Variant chr14-92005874-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5511.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (319/152324) while in subpopulation NFE AF= 0.00337 (229/68014). AF 95% confidence interval is 0.00301. There are 3 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIP11	NM_004239.4	c.2102A>G	p.Asn701Ser	missense_variant	Exon 11 of 21	ENST00000267622.8	NP_004230.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIP11	ENST00000267622.8	c.2102A>G	p.Asn701Ser	missense_variant	Exon 11 of 21	1	NM_004239.4	ENSP00000267622.4
TRIP11	ENST00000554357.5	c.1247A>G	p.Asn416Ser	missense_variant	Exon 5 of 15	1		ENSP00000451032.1

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00170 AC: 425 AN: 250624 Hom.: 0 AF XY: 0.00167 AC XY: 227 AN XY: 135546

Gnomad AFR exome AF: 0.000931

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00348 AC: 5092 AN: 1461716 Hom.: 15 Cov.: 32 AF XY: 0.00333 AC XY: 2423 AN XY: 727158

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00426

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00209 AC: 319 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00174 AC XY: 130 AN XY: 74500

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00337

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00318 Hom.: 1

Bravo AF: 0.00235

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00169 AC: 205

EpiCase AF: 0.00289

EpiControl AF: 0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Apr 28, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRIP11: BP4, BS2 -

Oct 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TRIP11 c.2102A>G; p.Asn701Ser variant (rs139539448), to our knowledge, is not described in the medical literature but contains an entry in ClinVar (Variation ID: 5511). It is observed in the general population at an overall frequency of 0.17% (484/282038 alleles) in the Genome Aggregation Database. The asparagine at position 701 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.037). However, due to limited clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. -

Achondrogenesis, type IA Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Connective tissue disorder Uncertain:1

Nov 07, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.5
DANN	Benign	0.41
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.037
Sift	Benign	0.29	T
Sift4G	Benign	0.20	T
Polyphen		0.0080	B
Vest4		0.036
MVP		0.24
MPC		0.082
ClinPred		0.0066	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.064

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: rs139539448; hg19: chr14-92472218; COSMIC: COSV99032633;