rs550137986

chr14-91974731-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004239.4(TRIP11):c.5470G>A(p.Asp1824Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000993 in 1,611,356 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TRIP11 NM_004239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16038212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIP11	NM_004239.4	c.5470G>A	p.Asp1824Asn	missense_variant	19/21	ENST00000267622.8
TRIP11	NM_001321851.1	c.5467G>A	p.Asp1823Asn	missense_variant	19/21
TRIP11	XM_047431935.1	c.4144G>A	p.Asp1382Asn	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIP11	ENST00000267622.8	c.5470G>A	p.Asp1824Asn	missense_variant	19/21	1	NM_004239.4	P1
TRIP11	ENST00000554357.5	c.4618G>A	p.Asp1540Asn	missense_variant	13/15	1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151312 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000730

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250164 Hom.: 1 AF XY: 0.0000148 AC XY: 2 AN XY: 135194

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1459924 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726248

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151432 Hom.: 1 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73926

Gnomad4 AFR AF: 0.0000728

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Achondrogenesis, type IA Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "C0"). In summary, this variant has uncertain impact on TRIP11 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with a TRIP11-related disease. This variant is present in population databases (rs550137986, ExAC 0.02%), including at least one homozygous individual. This sequence change replaces aspartate with asparagine at codon 1824 of the TRIP11 protein (p.Asp1824Asn). The  residue is moderately conserved and there is a small physicochemical difference between aspartate and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.078	T
Sift4G	Uncertain	0.011	D
Polyphen		0.97	D
Vest4		0.29
MutPred		0.54		Gain of MoRF binding (P = 0.0383);
MVP		0.68
MPC		0.30
ClinPred		0.31	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs550137986; hg19: chr14-92441075;