rs350132

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032551.5(KISS1R):c.1091T>A(p.Leu364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,356,162 control chromosomes in the GnomAD database, including 396,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48506 hom., cov: 33)

Exomes 𝑓: 0.76 ( 347977 hom. )

Consequence

KISS1R
NM_032551.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: -0.237

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.9137126E-7).

BP6

Variant 19-920642-T-A is Benign according to our data. Variant chr19-920642-T-A is described in ClinVar as [Benign]. Clinvar id is 447660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-920642-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1R	NM_032551.5 linkuse as main transcript	c.1091T>A	p.Leu364His	missense_variant	5/5	ENST00000234371.10	NP_115940.2	Q969F8
KISS1R	XM_047439545.1 linkuse as main transcript	c.1274T>A	p.Leu425His	missense_variant	4/4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10 linkuse as main transcript	c.1091T>A	p.Leu364His	missense_variant	5/5	1	NM_032551.5	ENSP00000234371.3		Q969F8
KISS1R	ENST00000606939.2 linkuse as main transcript	c.*177T>A		3_prime_UTR_variant	4/4	5		ENSP00000475639.1		U3KQ86

Frequencies

GnomAD3 genomes

AF:

0.796

AC:

120783

AN:

151762

Hom.:

48459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.897

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.721

Gnomad ASJ

AF:

0.821

Gnomad EAS

AF:

0.746

Gnomad SAS

AF:

0.742

Gnomad FIN

AF:

0.776

Gnomad MID

AF:

0.827

Gnomad NFE

AF:

0.760

Gnomad OTH

AF:

0.800

GnomAD3 exomes

AF:

0.781

AC:

9423

AN:

12060

Hom.:

3671

AF XY:

0.777

AC XY:

5669

AN XY:

7292

show subpopulations

Gnomad AFR exome

AF:

0.941

Gnomad AMR exome

AF:

0.746

Gnomad ASJ exome

AF:

0.842

Gnomad EAS exome

AF:

0.813

Gnomad SAS exome

AF:

0.740

Gnomad FIN exome

AF:

0.796

Gnomad NFE exome

AF:

0.779

Gnomad OTH exome

AF:

0.788

GnomAD4 exome

AF:

0.760

AC:

914936

AN:

1204292

Hom.:

347977

Cov.:

AF XY:

0.760

AC XY:

445591

AN XY:

586324

show subpopulations

Gnomad4 AFR exome

AF:

0.904

Gnomad4 AMR exome

AF:

0.737

Gnomad4 ASJ exome

AF:

0.837

Gnomad4 EAS exome

AF:

0.759

Gnomad4 SAS exome

AF:

0.752

Gnomad4 FIN exome

AF:

0.774

Gnomad4 NFE exome

AF:

0.754

Gnomad4 OTH exome

AF:

0.776

GnomAD4 genome

AF:

0.796

AC:

120887

AN:

151870

Hom.:

48506

Cov.:

AF XY:

0.795

AC XY:

59010

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.897

Gnomad4 AMR

AF:

0.720

Gnomad4 ASJ

AF:

0.821

Gnomad4 EAS

AF:

0.747

Gnomad4 SAS

AF:

0.743

Gnomad4 FIN

AF:

0.776

Gnomad4 NFE

AF:

0.760

Gnomad4 OTH

AF:

0.802

Alfa

AF:

0.782

Hom.:

5459

Bravo

AF:

0.796

TwinsUK

AF:

0.754

AC:

2794

ALSPAC

AF:

0.741

AC:

2856

ExAC

AF:

0.619

AC:

28075

Asia WGS

AF:

0.763

AC:

2655

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32228714, 27914139) -

Central precocious puberty 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

in vitro;research

National Institute for Research in Reproductive and Child Health, Indian Council of Medical Research

Augmented signaling through H364 KISS1R variant at high doses of kisspeptin contributing to central precocious puberty -

Hypogonadotropic hypogonadism 8 with or without anosmia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.1

DANN

Benign

0.82

DEOGEN2

Benign

0.14

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.14

MetaRNN

Benign

8.9e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.46

PrimateAI

Uncertain

0.76

PROVEAN

Benign

4.9

REVEL

Benign

0.090

Sift

Benign

1.0

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.039

MPC

1.1

ClinPred

0.00037

GERP RS

-0.61

Varity_R

0.069

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over