NM_001059.3:c.*73C>T

Variant names:

• chr4-103589609-G-A
• rs2765
• NM_001059.3:c.*73C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001059.3(TACR3):​c.*73C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,574,150 control chromosomes in the GnomAD database, including 317,480 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.62 (29952 hom., cov: 32)
  • Exomes 𝑓: 0.63 (287528 hom.)
• Consequence: TACR3 NM_001059.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.302
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACR3	NM_001059.3	c.*73C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000304883.3	NP_001050.1
TACR3-AS1	NR_186501.1	n.190-1598G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACR3	ENST00000304883.3	c.*73C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_001059.3	ENSP00000303325.2
TACR3-AS1	ENST00000502936.1	n.190-1598G>A		intron_variant	Intron 2 of 4	2
TACR3-AS1	ENST00000512401.5	n.292-1598G>A		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94849 AN: 151824 Hom.: 29928 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.618

GnomAD4 exome AF: 0.632 AC: 898918 AN: 1422208 Hom.: 287528 Cov.: 24 AF XY: 0.627 AC XY: 444821 AN XY: 709524

African (AFR) AF: 0.588 AC: 19182 AN: 32620

American (AMR) AF: 0.682 AC: 30358 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16572 AN: 25834

East Asian (EAS) AF: 0.477 AC: 18746 AN: 39286

South Asian (SAS) AF: 0.449 AC: 38180 AN: 85038

European-Finnish (FIN) AF: 0.747 AC: 38323 AN: 51326

Middle Eastern (MID) AF: 0.573 AC: 3207 AN: 5598

European-Non Finnish (NFE) AF: 0.647 AC: 698315 AN: 1079054

Other (OTH) AF: 0.611 AC: 36035 AN: 58962

GnomAD4 genome AF: 0.625 AC: 94915 AN: 151942 Hom.: 29952 Cov.: 32 AF XY: 0.625 AC XY: 46398 AN XY: 74264

African (AFR) AF: 0.592 AC: 24525 AN: 41414

American (AMR) AF: 0.625 AC: 9541 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.645 AC: 2238 AN: 3468

East Asian (EAS) AF: 0.472 AC: 2434 AN: 5158

South Asian (SAS) AF: 0.439 AC: 2111 AN: 4814

European-Finnish (FIN) AF: 0.758 AC: 7997 AN: 10548

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43914 AN: 67968

Other (OTH) AF: 0.618 AC: 1300 AN: 2104

Alfa AF: 0.632 Hom.: 103817

Bravo AF: 0.619

Asia WGS AF: 0.475 AC: 1654 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

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:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.35
DANN	Benign	0.29
PhyloP100		-0.30
Mutation Taster		=100/0	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: rs2765; hg19: chr4-104510766; COSMIC: COSV59200338;