NM_001059.3:c.-103T>C

Variant names:

• chr4-103719778-A-G
• rs3733632
• NM_001059.3:c.-103T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001059.3(TACR3):​c.-103T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,453,798 control chromosomes in the GnomAD database, including 44,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (13302 hom., cov: 32)
  • Exomes 𝑓: 0.19 (31563 hom.)
• Consequence: TACR3 NM_001059.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.13

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-103719778-A-G is Benign according to our data. Variant chr4-103719778-A-G is described in ClinVar as [Benign]. Clinvar id is 347119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACR3	NM_001059.3	c.-103T>C		5_prime_UTR_variant	Exon 1 of 5	ENST00000304883.3	NP_001050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACR3	ENST00000304883.3	c.-103T>C		5_prime_UTR_variant	Exon 1 of 5	1	NM_001059.3	ENSP00000303325.2

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51266 AN: 151940 Hom.: 13257 Cov.: 32

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.192 AC: 249952 AN: 1301740 Hom.: 31563 Cov.: 19 AF XY: 0.194 AC XY: 126097 AN XY: 648918

Gnomad4 AFR exome AF: 0.754

Gnomad4 AMR exome AF: 0.213

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.338 AC: 51369 AN: 152058 Hom.: 13302 Cov.: 32 AF XY: 0.338 AC XY: 25107 AN XY: 74342

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.173

Gnomad4 EAS AF: 0.361

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.176

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.308

Alfa AF: 0.189 Hom.: 7388

Bravo AF: 0.357

Asia WGS AF: 0.372 AC: 1298 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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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	-0.88
CADD	Benign	4.9
DANN	Benign	0.45

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: rs3733632; hg19: chr4-104640935;