Variant 1-204190556-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM2PP3_ModeratePP5_Moderate

The NM_002256.4(KISS1):c.345C>G(p.Asn115Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 30)

Consequence

KISS1
NM_002256.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.75

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1

Transcript NM_002256.4 (KISS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

PP5

Variant 1-204190556-G-C is Pathogenic according to our data. Variant chr1-204190556-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3381872.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1	NM_002256.4 linkuse as main transcript	c.345C>G	p.Asn115Lys	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.345C>G	p.Asn115Lys	missense_variant	3/3	1	NM_002256.4	ENSP00000356162.4		Q15726

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 13 with or without anosmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PM3+PP1_Strong+PP4+PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.48

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

2.0

M;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.2

D;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.83

MutPred

0.68

Gain of methylation at N115 (P = 0.0162);Gain of methylation at N115 (P = 0.0162);

MVP

0.65

MPC

0.43

ClinPred

1.0

GERP RS

3.8

Varity_R

0.88

gMVP

0.34

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over