4-103589735-C-T

Variant names:

• chr4-103589735-C-T
• rs17033889
• NM_001059.3:c.1345G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A449S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (55 hom.)
• Consequence: TACR3 NM_001059.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.19
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACR3	NM_001059.3	c.1345G>A	p.Ala449Thr	missense_variant	Exon 5 of 5	ENST00000304883.3	NP_001050.1
TACR3-AS1	NR_186501.1	n.190-1472C>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACR3	ENST00000304883.3	c.1345G>A	p.Ala449Thr	missense_variant	Exon 5 of 5	1	NM_001059.3	ENSP00000303325.2
TACR3-AS1	ENST00000502936.1	n.190-1472C>T		intron_variant	Intron 2 of 4	2
TACR3-AS1	ENST00000512401.5	n.292-1472C>T		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 731 AN: 152096 Hom.: 5 Cov.: 33

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

GnomAD2 exomes AF: 0.00532 AC: 1335 AN: 251110 AF XY: 0.00488

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 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.: 55 Cov.: 32 AF XY: 0.00640 AC XY: 4651 AN XY: 727128

African (AFR) AF: 0.00102 AC: 34 AN: 33456

American (AMR) AF: 0.00217 AC: 97 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26126

East Asian (EAS) AF: 0.0187 AC: 744 AN: 39688

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00215 AC: 115 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00758 AC: 8433 AN: 1111856

Other (OTH) AF: 0.00528 AC: 319 AN: 60378

GnomAD4 genome AF: 0.00480 AC: 731 AN: 152214 Hom.: 5 Cov.: 33 AF XY: 0.00445 AC XY: 331 AN XY: 74406

African (AFR) AF: 0.00132 AC: 55 AN: 41540

American (AMR) AF: 0.00340 AC: 52 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00704 AC: 479 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00658 Hom.: 11

Bravo AF: 0.00481

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00568 AC: 689

Asia WGS AF: 0.00924 AC: 32 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

Submissions by phenotype

not provided Benign:3

Mar 31, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23643382, 23329188, 27931036) -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypogonadotropic hypogonadism 11 with or without anosmia Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TACR3-related disorder Benign:1

Aug 10, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.068
MVP		0.69
MPC		0.31
ClinPred		0.0055	T
GERP RS		4.5
Varity_R		0.045
gMVP		0.35
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs17033889; hg19: chr4-104510892;