rs201464641

Variant names:

• chr1-204190413-CG-C
• rs201464641
• NM_002256.4:c.*70delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002256.4(KISS1):​c.*70delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0562 in 614,072 control chromosomes in the GnomAD database, including 1,918 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (828 hom., cov: 21)
  • Exomes 𝑓: 0.044 (1090 hom.)
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• Publications: 0 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]

REN (HGNC:9958): (renin) This gene encodes renin, an aspartic protease that is secreted by the kidneys. Renin is a part of the renin-angiotensin-aldosterone system involved in regulation of blood pressure, and electrolyte balance. This enzyme catalyzes the first step in the activation pathway of angiotensinogen by cleaving angiotensinogen to form angiotensin I, which is then converted to angiotensin II by angiotensin I converting enzyme. This cascade can result in aldosterone release, narrowing of blood vessels, and increase in blood pressure as angiotension II is a vasoconstrictive peptide. Transcript variants that encode different protein isoforms and that arise from alternative splicing and the use of alternative promoters have been described, but their full-length nature has not been determined. Mutations in this gene have been shown to cause hyperuricemic nephropathy familial juvenile 2, familial hyperproreninemia, and renal tubular dysgenesis. [provided by RefSeq, May 2020]

REN Gene-Disease associations (from GenCC):

• familial juvenile hyperuricemic nephropathy type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-204190413-CG-C is Benign according to our data. Variant chr1-204190413-CG-C is described in ClinVar as Benign. ClinVar VariationId is 1247896.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	NM_002256.4	MANE Select	c.*70delC		3_prime_UTR	Exon 3 of 3	NP_002247.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	ENST00000367194.5	TSL:1 MANE Select	c.*70delC		3_prime_UTR	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.*70delC		3_prime_UTR	Exon 2 of 2	ENSP00000552504.1
	REN	ENST00000638118.1	TSL:5	c.-393delC		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 13298 AN: 132244 Hom.: 828 Cov.: 21

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0721

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0381

Gnomad SAS AF: 0.0566

Gnomad FIN AF: 0.0882

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0927

Gnomad OTH AF: 0.0902

GnomAD4 exome AF: 0.0440 AC: 21193 AN: 481756 Hom.: 1090 Cov.: 4 AF XY: 0.0441 AC XY: 11488 AN XY: 260736

African (AFR) AF: 0.108 AC: 1016 AN: 9372

American (AMR) AF: 0.0334 AC: 902 AN: 27016

Ashkenazi Jewish (ASJ) AF: 0.0466 AC: 760 AN: 16318

East Asian (EAS) AF: 0.0143 AC: 377 AN: 26422

South Asian (SAS) AF: 0.0467 AC: 2742 AN: 58692

European-Finnish (FIN) AF: 0.0461 AC: 1244 AN: 26974

Middle Eastern (MID) AF: 0.0521 AC: 99 AN: 1900

European-Non Finnish (NFE) AF: 0.0446 AC: 12933 AN: 289812

Other (OTH) AF: 0.0444 AC: 1120 AN: 25250

GnomAD4 genome AF: 0.101 AC: 13299 AN: 132316 Hom.: 828 Cov.: 21 AF XY: 0.0985 AC XY: 6335 AN XY: 64334

African (AFR) AF: 0.145 AC: 4687 AN: 32290

American (AMR) AF: 0.0719 AC: 972 AN: 13520

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 325 AN: 3166

East Asian (EAS) AF: 0.0380 AC: 155 AN: 4080

South Asian (SAS) AF: 0.0562 AC: 243 AN: 4324

European-Finnish (FIN) AF: 0.0882 AC: 814 AN: 9230

Middle Eastern (MID) AF: 0.0956 AC: 26 AN: 272

European-Non Finnish (NFE) AF: 0.0927 AC: 5816 AN: 62720

Other (OTH) AF: 0.0892 AC: 166 AN: 1860

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs201464641; hg19: chr1-204159541;