4-103589834-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001059.3(TACR3):c.1246A>T(p.Asn416Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,613,920 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: TACR3 NM_001059.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.69

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043549538).
• BP6: Variant 4-103589834-T-A is Benign according to our data. Variant chr4-103589834-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 347107.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00145 (220/152220) while in subpopulation NFE AF= 0.00107 (73/68006). AF 95% confidence interval is 0.000875. There are 2 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TACR3	NM_001059.3	c.1246A>T	p.Asn416Tyr	missense_variant	5/5	ENST00000304883.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TACR3	ENST00000304883.3	c.1246A>T	p.Asn416Tyr	missense_variant	5/5	1	NM_001059.3	P1
TACR3-AS1	ENST00000502936.1	n.190-1373T>A		intron_variant, non_coding_transcript_variant		2
TACR3-AS1	ENST00000512401.5	n.292-1373T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152102 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00145 AC: 365 AN: 251186 Hom.: 1 AF XY: 0.00147 AC XY: 200 AN XY: 135740

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00115 AC: 1681 AN: 1461700 Hom.: 2 Cov.: 32 AF XY: 0.00111 AC XY: 805 AN XY: 727150

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00906

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00145 AC: 220 AN: 152220 Hom.: 2 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74434

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	TACR3: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Hypogonadotropic hypogonadism 11 with or without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 10, 2018

- -

TACR3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2020

This variant is classified as likely 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	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Benign	0.93
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.035	D
Polyphen		0.24	B
Vest4		0.10
MVP		0.85
MPC		0.41
ClinPred		0.039	T
GERP RS		4.4
Varity_R		0.068
gMVP		0.39

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

Other links and lift over

dbSNP: rs143073792; hg19: chr4-104510991;