1-204190552-A-G

Position:

chr1-204190552-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002256.4(KISS1):c.349T>C(p.Phe117Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,608,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

KISS1
NM_002256.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.52

Variant links:

Genes affected

KISS1 (HGNC:6341): (KiSS-1 metastasis suppressor) This gene is a metastasis suppressor gene that suppresses metastases of melanomas and breast carcinomas without affecting tumorigenicity. The encoded protein may inhibit chemotaxis and invasion and thereby attenuate metastasis in malignant melanomas. Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. A protein product of this gene, kisspeptin, stimulates gonadotropin-releasing hormone (GnRH)-induced gonadotropin secretion and regulates the pubertal activation of GnRH neurons. A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues. [provided by RefSeq, Jun 2022]

KISS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34300786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1	NM_002256.4 linkuse as main transcript	c.349T>C	p.Phe117Leu	missense_variant	3/3	ENST00000367194.5	NP_002247.3	Q15726

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1	ENST00000367194.5 linkuse as main transcript	c.349T>C	p.Phe117Leu	missense_variant	3/3	1	NM_002256.4	ENSP00000356162.4		Q15726

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000181

AC:

AN:

232500

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

127952

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000407

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000196

AC:

286

AN:

1456728

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

144

AN XY:

724238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000116

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000158

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000185

ExAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 117 of the KISS1 protein (p.Phe117Leu). This variant is present in population databases (rs199666322, gnomAD 0.04%). This missense change has been observed in individual(s) with hypogonadotropic hypogonadism (PMID: 21880801, 29419413). ClinVar contains an entry for this variant (Variation ID: 1303092). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects KISS1 function (PMID: 21880801). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2019	Identified in the heterozygous state in patients with normosmic idiopathic hypogonadotropic hypogonadism in the published literature, however, this variant was also detected at a similar frequency in control populations (Chan et al., 2011; Cassatella et al., 2018); Published functional studies demonstrate a damaging effect with reduced inositol phosphate generation (Chan et al., 2011); This variant is associated with the following publications: (PMID: 21880801, 29419413) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

D;T

Eigen

Benign

-0.024

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.59

T;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.34

T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Pathogenic

0.69

Sift

Benign

0.069

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.36

B;.

Vest4

0.50

MutPred

0.70

Gain of MoRF binding (P = 0.1162);Gain of MoRF binding (P = 0.1162);

MVP

0.99

MPC

0.10

ClinPred

0.43

GERP RS

4.7

Varity_R

0.40

gMVP

0.12

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