4-103589759-G-A

Position:

chr4-103589759-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001059.3(TACR3):c.1321C>T(p.Arg441Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,850 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TACR3
NM_001059.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.809

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:

TACR3-AS1 (HGNC:55593): (TACR3 antisense RNA 1)

TACR3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007983953).

BP6

Variant 4-103589759-G-A is Benign according to our data. Variant chr4-103589759-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586774.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TACR3	NM_001059.3 linkuse as main transcript	c.1321C>T	p.Arg441Cys	missense_variant	5/5	ENST00000304883.3	NP_001050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TACR3	ENST00000304883.3 linkuse as main transcript	c.1321C>T	p.Arg441Cys	missense_variant	5/5	1	NM_001059.3	ENSP00000303325	P1
TACR3-AS1	ENST00000502936.1 linkuse as main transcript	n.190-1448G>A		intron_variant, non_coding_transcript_variant		2
TACR3-AS1	ENST00000512401.5 linkuse as main transcript	n.292-1448G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00866

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000330

AC:

AN:

251254

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000244

AC:

356

AN:

1461670

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00677

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000126

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000230

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00866

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000367

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2023	Reported in a patient with Kallman syndrome in the published literature (PMID: 22035731); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22035731) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2018	- -

Hypogonadotropic hypogonadism 11 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.31

M_CAP

Benign

0.023

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

0.62

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.025

Polyphen

0.0040

Vest4

0.075

MVP

0.74

MPC

0.44

ClinPred

0.098

GERP RS

2.6

Varity_R

0.15

gMVP

0.41

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

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