rs141553918

Positions:

• chr14-92021762-C-A

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.382G>T​(p.Ala128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,614,164 control chromosomes in the GnomAD database, including 4 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: TRIP11 NM_004239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.840

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012328416).
• BP6: Variant 14-92021762-C-A is Benign according to our data. Variant chr14-92021762-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197230.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}. Variant chr14-92021762-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00132 (201/152294) while in subpopulation AMR AF= 0.00301 (46/15288). AF 95% confidence interval is 0.00232. There are 0 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIP11	NM_004239.4	c.382G>T	p.Ala128Ser	missense_variant	4/21	ENST00000267622.8	NP_004230.2
TRIP11	NM_001321851.1	c.379G>T	p.Ala127Ser	missense_variant	4/21		NP_001308780.1
TRIP11	XR_001750598.3	n.756G>T		non_coding_transcript_exon_variant	4/15
TRIP11	XR_943560.3	n.756G>T		non_coding_transcript_exon_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIP11	ENST00000267622.8	c.382G>T	p.Ala128Ser	missense_variant	4/21	1	NM_004239.4	ENSP00000267622.4
TRIP11	ENST00000555516.6	c.-102G>T		5_prime_UTR_variant	4/6	5		ENSP00000451944.1

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000891 AC: 224 AN: 251332 Hom.: 1 AF XY: 0.00103 AC XY: 140 AN XY: 135836

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00159 AC: 2321 AN: 1461870 Hom.: 4 Cov.: 32 AF XY: 0.00154 AC XY: 1123 AN XY: 727238

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74468

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00153

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2021	- -

Achondrogenesis, type IA Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Connective tissue disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.8
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.021	D
Polyphen		0.47	P
Vest4		0.36
MVP		0.59
MPC		0.18
ClinPred		0.042	T
GERP RS		2.4
Varity_R		0.063
gMVP		0.25

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: rs141553918; hg19: chr14-92488106; COSMIC: COSV99971415; COSMIC: COSV99971415;