4-103589735-C-T

Position:

chr4-103589735-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001059.3(TACR3):c.1345G>A(p.Ala449Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0065 in 1,613,872 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0067 ( 55 hom. )

Consequence

TACR3
NM_001059.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.19

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026733577).

BP6

Variant 4-103589735-C-T is Benign according to our data. Variant chr4-103589735-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0048 (731/152214) while in subpopulation EAS AF= 0.0201 (104/5172). AF 95% confidence interval is 0.017. There are 5 homozygotes in gnomad4. There are 331 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TACR3	NM_001059.3 linkuse as main transcript	c.1345G>A	p.Ala449Thr	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.1345G>A	p.Ala449Thr	missense_variant	5/5	1	NM_001059.3	ENSP00000303325	P1
TACR3-AS1	ENST00000502936.1 linkuse as main transcript	n.190-1472C>T		intron_variant, non_coding_transcript_variant		2
TACR3-AS1	ENST00000512401.5 linkuse as main transcript	n.292-1472C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00481

AC:

731

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00341

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0201

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00704

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00532

AC:

1335

AN:

251110

Hom.:

AF XY:

0.00488

AC XY:

663

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0205

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.00707

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00667

AC:

9753

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00640

AC XY:

4651

AN XY:

727128

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00217

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0187

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00215

Gnomad4 NFE exome

AF:

0.00758

Gnomad4 OTH exome

AF:

0.00528

GnomAD4 genome

AF:

0.00480

AC:

731

AN:

152214

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0201

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00704

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00652

Hom.:

Bravo

AF:

0.00481

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00568

AC:

689

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00622

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2020	This variant is associated with the following publications: (PMID: 23643382, 23329188, 27931036) -

Hypogonadotropic hypogonadism 11 with or without anosmia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -

TACR3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.058

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

0.62

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.068

MVP

0.69

MPC

0.31

ClinPred

0.0055

GERP RS

4.5

Varity_R

0.045

gMVP

0.35

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