rs71745629

chr1-204190483-CT-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_002256.4(KISS1):c.417del(p.Ter139TrpfsTer8) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,600,964 control chromosomes in the GnomAD database, including 39,128 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3189 hom., cov: 23)
  • Exomes 𝑓: 0.22 (35939 hom.)
• Consequence: KISS1 NM_002256.4 frameshift, stop_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0270

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 144 codons.
• BP6: Variant 1-204190483-CT-C is Benign according to our data. Variant chr1-204190483-CT-C is described in ClinVar as [Benign]. Clinvar id is 403018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-204190483-CT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KISS1	NM_002256.4	c.417del	p.Ter139TrpfsTer8	frameshift_variant, stop_lost	3/3	ENST00000367194.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KISS1	ENST00000367194.5	c.417del	p.Ter139TrpfsTer8	frameshift_variant, stop_lost	3/3	1	NM_002256.4	P1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28714 AN: 151302 Hom.: 3186 Cov.: 23

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.228 AC: 50085 AN: 219744 Hom.: 6227 AF XY: 0.226 AC XY: 27382 AN XY: 121428

Gnomad AFR exome AF: 0.0860

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.411

Gnomad SAS exome AF: 0.202

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.218 AC: 315301 AN: 1449544 Hom.: 35939 Cov.: 31 AF XY: 0.217 AC XY: 156309 AN XY: 720374

Gnomad4 AFR exome AF: 0.0854

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.190 AC: 28730 AN: 151420 Hom.: 3189 Cov.: 23 AF XY: 0.191 AC XY: 14141 AN XY: 73964

Gnomad4 AFR AF: 0.0948

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.203

Alfa AF: 0.132 Hom.: 299

Bravo AF: 0.191

Asia WGS AF: 0.275 AC: 953 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 1842/11014=16.7% -

Hypogonadotropic hypogonadism 13 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs71745629; hg19: chr1-204159611; COSMIC: COSV65816897; COSMIC: COSV65816897;