chr19-920642-T-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.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. 15/21 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

Publications

30 publications found

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 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=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 VariationId is 447660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1R	NM_032551.5 link	c.1091T>A	p.Leu364His	missense_variant	Exon 5 of 5	ENST00000234371.10	NP_115940.2	Q969F8
KISS1R	XM_047439545.1 link	c.1274T>A	p.Leu425His	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.1091T>A	p.Leu364His	missense_variant	Exon 5 of 5	1	NM_032551.5	ENSP00000234371.3		Q969F8
KISS1R	ENST00000606939.2 link	c.*177T>A		3_prime_UTR_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.781

AC:

9423

AN:

12060

AF XY:

0.777

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 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

African (AFR)

AF:

0.904

AC:

21661

AN:

23962

American (AMR)

AF:

0.737

AC:

7721

AN:

10482

Ashkenazi Jewish (ASJ)

AF:

0.837

AC:

13820

AN:

16520

East Asian (EAS)

AF:

0.759

AC:

21168

AN:

27886

South Asian (SAS)

AF:

0.752

AC:

34589

AN:

45994

European-Finnish (FIN)

AF:

0.774

AC:

22671

AN:

29278

Middle Eastern (MID)

AF:

0.788

AC:

3311

AN:

4202

European-Non Finnish (NFE)

AF:

0.754

AC:

751419

AN:

996262

Other (OTH)

AF:

0.776

AC:

38576

AN:

49706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

12962

25924

38885

51847

64809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19502

39004

58506

78008

97510

<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:

0.796

AC:

120887

AN:

151870

Hom.:

48506

Cov.:

AF XY:

0.795

AC XY:

59010

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.897

AC:

37217

AN:

41492

American (AMR)

AF:

0.720

AC:

10988

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.821

AC:

2849

AN:

3470

East Asian (EAS)

AF:

0.747

AC:

3840

AN:

5144

South Asian (SAS)

AF:

0.743

AC:

3588

AN:

4830

European-Finnish (FIN)

AF:

0.776

AC:

8144

AN:

10500

Middle Eastern (MID)

AF:

0.828

AC:

240

AN:

290

European-Non Finnish (NFE)

AF:

0.760

AC:

51614

AN:

67876

Other (OTH)

AF:

0.802

AC:

1686

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1286

2571

3857

5142

6428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.782

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

Jul 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32228714, 27914139) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central precocious puberty 1

Pathogenic:1

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:in vitro;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

Jul 14, 2021

Genome-Nilou Lab

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

0.062

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

3.1

(source)

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

PhyloP100

-0.24

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

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over