rs146482011

chr4-103589759-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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. 13/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.809

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 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, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TACR3	NM_001059.3	c.1321C>T	p.Arg441Cys	missense_variant	5/5	ENST00000304883.3

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152180 Hom.: 1 Cov.: 33

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: 83 AN: 251254 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135794

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.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 176 AN XY: 727132

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: 35 AN: 152180 Hom.: 1 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74322

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.: 0

Bravo AF: 0.000268

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2020	Reported in a patient with Kallman syndrome in the published literature (Quaynor et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22035731) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 03, 2023	- -

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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	0.62	D
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.025	D
Polyphen		0.0040	B
Vest4		0.075
MVP		0.74
MPC		0.44
ClinPred		0.098	T
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

Other links and lift over

dbSNP: rs146482011; hg19: chr4-104510916; COSMIC: COSV59202356;