4-103589735-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 16/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.19

Publications

16 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 links:

TACR3-AS1 (HGNC:55593): (TACR3 antisense RNA 1)

TACR3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001059.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TACR3	NM_001059.3	MANE Select	c.1345G>A	p.Ala449Thr	missense	Exon 5 of 5	NP_001050.1	P29371
	TACR3-AS1	NR_186501.1		n.190-1472C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TACR3	ENST00000304883.3	TSL:1 MANE Select	c.1345G>A	p.Ala449Thr	missense	Exon 5 of 5	ENSP00000303325.2	P29371
TACR3-AS1	ENST00000502936.1	TSL:2	n.190-1472C>T		intron	N/A
TACR3-AS1	ENST00000512401.5	TSL:2	n.292-1472C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00481

AC:

731

AN:

152096

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00532

AC:

1335

AN:

251110

AF XY:

0.00488

show subpopulations

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 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.:

Cov.:

AF XY:

0.00640

AC XY:

4651

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33456

American (AMR)

AF:

0.00217

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26126

East Asian (EAS)

AF:

0.0187

AC:

744

AN:

39688

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00215

AC:

115

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00758

AC:

8433

AN:

1111856

Other (OTH)

AF:

0.00528

AC:

319

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

586

1172

1757

2343

2929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.00480

AC:

731

AN:

152214

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

331

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41540

American (AMR)

AF:

0.00340

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0201

AC:

104

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00704

AC:

479

AN:

68012

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

115

154

192

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:

0.00658

Hom.:

Bravo

AF:

0.00481

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00568

AC:

689

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00583

EpiControl

AF:

0.00622

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hypogonadotropic hypogonadism 11 with or without anosmia (2)

TACR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.058

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.11

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

PhyloP100

2.2

PrimateAI

Benign

0.36

PROVEAN

Benign

0.62

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.068

MVP

0.69

MPC

0.31

ClinPred

0.0055

GERP RS

4.5

Varity_R

0.045

gMVP

0.35

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over