NM_032551.5:c.565G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032551.5(KISS1R):c.565G>A(p.Ala189Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,564,126 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 73 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 78 hom. )

Consequence

KISS1R
NM_032551.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.74

Publications

12 publications found

Variant links:

COSMIC-nc: COSV107239900

Genes affected

KISS1R (HGNC:4510): (KISS1 receptor) The protein encoded by this gene is a galanin-like G protein-coupled receptor that binds metastin, a peptide encoded by the metastasis suppressor gene KISS1. The tissue distribution of the expressed gene suggests that it is involved in the regulation of endocrine function, and this is supported by the finding that this gene appears to play a role in the onset of puberty. Mutations in this gene have been associated with hypogonadotropic hypogonadism and central precocious puberty. [provided by RefSeq, Jul 2008]

KISS1R Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 8 with or without anosmia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
central precocious puberty 1
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KISS1R 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=0.0017435253).

BP6

Variant 19-919933-G-A is Benign according to our data. Variant chr19-919933-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1R	NM_032551.5 link	c.565G>A	p.Ala189Thr	missense_variant	Exon 4 of 5	ENST00000234371.10	NP_115940.2	Q969F8
KISS1R	XM_047439545.1 link	c.565G>A	p.Ala189Thr	missense_variant	Exon 4 of 4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10 link	c.565G>A	p.Ala189Thr	missense_variant	Exon 4 of 5	1	NM_032551.5	ENSP00000234371.3		Q969F8
KISS1R	ENST00000606939.2 link	c.505+308G>A		intron_variant	Intron 3 of 3	5		ENSP00000475639.1		U3KQ86

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2717

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0600

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00456

AC:

756

AN:

165870

AF XY:

0.00380

show subpopulations

Gnomad AFR exome

AF:

0.0675

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000374

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00249

AC:

3510

AN:

1411886

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1584

AN XY:

699166

show subpopulations

African (AFR)

AF:

0.0628

AC:

2014

AN:

32058

American (AMR)

AF:

0.00345

AC:

139

AN:

40284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.0000273

AC:

AN:

36666

South Asian (SAS)

AF:

0.000185

AC:

AN:

81150

European-Finnish (FIN)

AF:

0.000241

AC:

AN:

41462

Middle Eastern (MID)

AF:

0.00456

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000929

AC:

1013

AN:

1090552

Other (OTH)

AF:

0.00499

AC:

292

AN:

58560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

206

412

619

825

1031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0179

AC:

2725

AN:

152240

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1299

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0600

AC:

2492

AN:

41544

American (AMR)

AF:

0.00863

AC:

132

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

67998

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

146

291

437

582

728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00722

Hom.:

Bravo

AF:

0.0202

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0428

AC:

176

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00404

AC:

464

Asia WGS

AF:

0.00491

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 05, 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

- -

Apr 25, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 26, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 03, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.9

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.081

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.5

PhyloP100

1.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

2.3

REVEL

Benign

0.078

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.034

MVP

0.39

MPC

0.86

ClinPred

0.0015

GERP RS

2.5

Varity_R

0.054

gMVP

0.28

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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