rs2276973

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001059.3(TACR3):c.857A>G(p.Lys286Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,020 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 23 hom. )

Consequence

TACR3
NM_001059.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.46

Publications

11 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 11 with or without anosmia
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TACR3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 4-103656225-T-C is Benign according to our data. Variant chr4-103656225-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0084 (1278/152162) while in subpopulation AFR AF = 0.0246 (1024/41554). AF 95% confidence interval is 0.0234. There are 14 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACR3	NM_001059.3 link	c.857A>G	p.Lys286Arg	missense_variant	Exon 3 of 5	ENST00000304883.3	NP_001050.1	P29371

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACR3	ENST00000304883.3 link	c.857A>G	p.Lys286Arg	missense_variant	Exon 3 of 5	1	NM_001059.3	ENSP00000303325.2		P29371

Frequencies

GnomAD3 genomes

AF:

0.00834

AC:

1268

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00682

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00367

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00340

AC:

854

AN:

250988

AF XY:

0.00290

show subpopulations

Gnomad AFR exome

AF:

0.0237

Gnomad AMR exome

AF:

0.00449

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00199

AC:

2911

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1432

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.0278

AC:

930

AN:

33406

American (AMR)

AF:

0.00495

AC:

221

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00215

AC:

AN:

26086

East Asian (EAS)

AF:

0.00298

AC:

118

AN:

39632

South Asian (SAS)

AF:

0.000545

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.0155

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00105

AC:

1163

AN:

1111316

Other (OTH)

AF:

0.00471

AC:

284

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00840

AC:

1278

AN:

152162

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

613

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0246

AC:

1024

AN:

41554

American (AMR)

AF:

0.00682

AC:

104

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00368

AC:

AN:

5170

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

67956

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00478

Hom.:

Bravo

AF:

0.00963

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00371

AC:

451

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 11 with or without anosmia

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Nov 08, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Aug 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 17, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Feb 20, 2017

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. -

May 16, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.077

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

3.5

PrimateAI

Uncertain

0.51

PROVEAN

Benign

1.1

REVEL

Benign

0.082

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.070

MVP

0.57

MPC

0.28

ClinPred

0.010

GERP RS

3.3

Varity_R

0.078

gMVP

0.32

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over