rs2276973

chr4-103656225-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001059.3(TACR3):c.857A>G(p.Lys286Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,020 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (23 hom.)
• Consequence: TACR3 NM_001059.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.46

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065711737).
• BP6: Variant 4-103656225-T-C is Benign according to our data. Variant chr4-103656225-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 445619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-103656225-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0084 (1278/152162) while in subpopulation AFR AF= 0.0246 (1024/41554). AF 95% confidence interval is 0.0234. There are 14 homozygotes in gnomad4. There are 613 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TACR3	NM_001059.3	c.857A>G	p.Lys286Arg	missense_variant	3/5	ENST00000304883.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TACR3	ENST00000304883.3	c.857A>G	p.Lys286Arg	missense_variant	3/5	1	NM_001059.3	P1

Frequencies

GnomAD3 genomes AF: 0.00834 AC: 1268 AN: 152044 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00682

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00367

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00340 AC: 854 AN: 250988 Hom.: 5 AF XY: 0.00290 AC XY: 394 AN XY: 135646

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00392

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00199 AC: 2911 AN: 1460858 Hom.: 23 Cov.: 31 AF XY: 0.00197 AC XY: 1432 AN XY: 726738

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00495

Gnomad4 ASJ exome AF: 0.00215

Gnomad4 EAS exome AF: 0.00298

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00471

GnomAD4 genome AF: 0.00840 AC: 1278 AN: 152162 Hom.: 14 Cov.: 32 AF XY: 0.00824 AC XY: 613 AN XY: 74384

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00682

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00368

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00374 Hom.: 8

Bravo AF: 0.00963

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00371 AC: 451

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypogonadotropic hypogonadism 11 with or without anosmia Benign:3

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 08, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 17, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 20, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	20
Dann	Benign	0.20
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.082
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.070
MVP		0.57
MPC		0.28
ClinPred		0.010	T
GERP RS		3.3
Varity_R		0.078
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2276973; hg19: chr4-104577382; COSMIC: COSV59201897;