rs144292455

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001059.3(TACR3):c.824G>A(p.Trp275Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000463 in 1,612,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

TACR3
NM_001059.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.97

Variant links:

Genes affected

TACR3 (HGNC:11528): (tachykinin receptor 3) This gene belongs to a family of genes that function as receptors for tachykinins. Receptor affinities are specified by variations in the 5'-end of the sequence. The receptors belonging to this family are characterized by interactions with G proteins and 7 hydrophobic transmembrane regions. This gene encodes the receptor for the tachykinin neurokinin 3, also referred to as neurokinin B. [provided by RefSeq, Jul 2008]

TACR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-103656258-C-T is Pathogenic according to our data. Variant chr4-103656258-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 66084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-103656258-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TACR3	NM_001059.3 linkuse as main transcript	c.824G>A	p.Trp275Ter	stop_gained	3/5	ENST00000304883.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TACR3	ENST00000304883.3 linkuse as main transcript	c.824G>A	p.Trp275Ter	stop_gained	3/5	1	NM_001059.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000307

AC:

AN:

250942

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000626

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000472

AC:

690

AN:

1460918

Hom.:

Cov.:

AF XY:

0.000466

AC XY:

339

AN XY:

726780

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000591

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000375

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000765

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000645

Hom.:

Bravo

AF:

0.000382

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000711

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2019	DNA sequence analysis of the TACR3 gene demonstrated an apparently homozygous sequence change, c.824G>A, which results in the creation of a premature stop codon at amino acid position 275, p.Trp275*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TACR3 protein with potentially abnormal function. This sequence change has been previously described in male patients with normosmic idiopathic hypogonadotropic hypogonadism in both homozygous and compound heterozygous state (Francou et al., 2011 and Gianetti et al., 2010). This sequence change has been described in the gnomAD database with a population frequency of 0.032% (rs144292455). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 27, 2022	This sequence change creates a premature translational stop signal (p.Trp275*) in the TACR3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TACR3 are known to be pathogenic (PMID: 20194706, 20332248, 22031817). This variant is present in population databases (rs144292455, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with idiopathic hypogonadotropic hypogonadism (PMID: 33363893). ClinVar contains an entry for this variant (Variation ID: 66084). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29419413, 29886503, 31200363, 23643382, 21300340, 25525159, 26207952, 28436984, 30665703, 23329188, 30450471, 20332248, 26792935, 26239645, 22035731, 31980526, 34426522, 33363893, 31589614, 34055685, 22031817) -

Hypogonadotropic hypogonadism 11 with or without anosmia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TACR3 c.824G>A (p.Trp275Ter) variant is a stop-gained variant reported in four studies in which it is found in a total of 13 individuals with isolated gonadotropin-releasing hormone (GnRH) deficiency, including in three homozygotes, in three compound heterozygotes, in five heterozygotes, and in two individuals showing digenic inheritance (Gianetti et al. 2010; Quaynor et al. 2011; Xu et al. 2011; Francou et al. 2011). The variant was absent from over 800 controls, but is reported at a frequency of 0.00093 in the European American population of the Exome Sequencing Project. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Trp275Ter variant is classified as pathogenic for isolated GnRH deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.66

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

Vest4

0.97

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.44

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over