4-103589735-C-T

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.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 (★★). 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:5
• Conservation: PhyloP100: 2.19

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 -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 GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TACR3	NM_001059.3	c.1345G>A	p.Ala449Thr	missense_variant	5/5	ENST00000304883.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TACR3	ENST00000304883.3	c.1345G>A	p.Ala449Thr	missense_variant	5/5	1	NM_001059.3	P1
TACR3-AS1	ENST00000502936.1	n.190-1472C>T		intron_variant, non_coding_transcript_variant		2
TACR3-AS1	ENST00000512401.5	n.292-1472C>T		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.00532 AC: 1335 AN: 251110 Hom.: 7 AF XY: 0.00488 AC XY: 663 AN XY: 135726

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

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.: 5 Cov.: 33 AF XY: 0.00445 AC XY: 331 AN XY: 74406

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.: 6

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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) -

TACR3-related disorder Benign:1

Benign, criteria provided, single submitter

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	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
MutationTaster	Benign	1.0	N
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

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: rs17033889; hg19: chr4-104510892;