rs350132

chr19-920642-T-Achr19-920642-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: -0.237

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]

ACMG classification

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	UniProt
KISS1R	NM_032551.5	c.1091T>A	p.Leu364His	missense_variant	5/5	ENST00000234371.10
KISS1R	XM_047439545.1	c.1274T>A	p.Leu425His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KISS1R	ENST00000234371.10	c.1091T>A	p.Leu364His	missense_variant	5/5	1	NM_032551.5	P1
KISS1R	ENST00000606939.2	c.*177T>A		3_prime_UTR_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120783 AN: 151762 Hom.: 48459 Cov.: 33

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

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.: 57 AF XY: 0.760 AC XY: 445591 AN XY: 586324

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.: 33 AF XY: 0.795 AC XY: 59010 AN XY: 74256

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:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32228714, 27914139) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Centra 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	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	3.1
Dann	Benign	0.82
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.46	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	4.9	N
REVEL	Benign	0.090
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.039
MPC		1.1
ClinPred		0.00037	T
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

Other links and lift over

dbSNP: rs350132; hg19: chr19-920642; COSMIC: COSV52257058; COSMIC: COSV52257058;