NM_001059.3:c.*138G>A

Variant names:

• chr4-103589544-C-T
• rs200193311
• NM_001059.3:c.*138G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001059.3(TACR3):​c.*138G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000959 in 888,014 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: TACR3 NM_001059.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.300
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00067 (102/152266) while in subpopulation SAS AF = 0.00705 (34/4824). AF 95% confidence interval is 0.00518. There are 2 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACR3	NM_001059.3	c.*138G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000304883.3	NP_001050.1
TACR3-AS1	NR_186501.1	n.190-1663C>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACR3	ENST00000304883.3	c.*138G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_001059.3	ENSP00000303325.2
TACR3-AS1	ENST00000502936.1	n.190-1663C>T		intron_variant	Intron 2 of 4	2
TACR3-AS1	ENST00000512401.5	n.292-1663C>T		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152148 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00102 AC: 750 AN: 735748 Hom.: 4 Cov.: 10 AF XY: 0.00122 AC XY: 465 AN XY: 379930

African (AFR) AF: 0.000110 AC: 2 AN: 18104

American (AMR) AF: 0.000439 AC: 13 AN: 29634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18484

East Asian (EAS) AF: 0.0000304 AC: 1 AN: 32864

South Asian (SAS) AF: 0.00580 AC: 350 AN: 60330

European-Finnish (FIN) AF: 0.0000556 AC: 2 AN: 35940

Middle Eastern (MID) AF: 0.00519 AC: 15 AN: 2890

European-Non Finnish (NFE) AF: 0.000666 AC: 334 AN: 501840

Other (OTH) AF: 0.000925 AC: 33 AN: 35662

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152266 Hom.: 2 Cov.: 33 AF XY: 0.000846 AC XY: 63 AN XY: 74434

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.00111 AC: 17 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000563

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 11 with or without anosmia Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.74
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: rs200193311; hg19: chr4-104510701;