1-204192463-T-C

Variant names:

• chr1-204192463-T-C
• rs2510
• NM_002256.4:c.103+311A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002256.4(KISS1):​c.103+311A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 151,466 control chromosomes in the GnomAD database, including 6,645 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6645 hom., cov: 30)
• Consequence: KISS1 NM_002256.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 13 with or without anosmia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002256.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	NM_002256.4	MANE Select	c.103+311A>G		intron	N/A	NP_002247.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	ENST00000367194.5	TSL:1 MANE Select	c.103+311A>G		intron	N/A	ENSP00000356162.4

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43768 AN: 151350 Hom.: 6637 Cov.: 30

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.283

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.289 AC: 43813 AN: 151466 Hom.: 6645 Cov.: 30 AF XY: 0.287 AC XY: 21264 AN XY: 73994

African (AFR) AF: 0.351 AC: 14441 AN: 41168

American (AMR) AF: 0.316 AC: 4814 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1012 AN: 3470

East Asian (EAS) AF: 0.430 AC: 2209 AN: 5132

South Asian (SAS) AF: 0.231 AC: 1110 AN: 4796

European-Finnish (FIN) AF: 0.217 AC: 2266 AN: 10466

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 17027 AN: 67888

Other (OTH) AF: 0.285 AC: 600 AN: 2104

Alfa AF: 0.266 Hom.: 4137

Bravo AF: 0.302

Asia WGS AF: 0.322 AC: 1117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.31
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2510; hg19: chr1-204161591;