rs71745629

Variant names:

• chr1-204190483-CT-C
• rs71745629
• NM_002256.4:c.417delA

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_002256.4(KISS1):​c.417delA​(p.Ter139fs) 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
• Publications: 20 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• renal tubular dysgenesis of genetic origin

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Stoplost variant in NM_002256.4
• BP6: Variant 1-204190483-CT-C is Benign according to our data. Variant chr1-204190483-CT-C is described in ClinVar as Benign. ClinVar VariationId is 403018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
KISS1	NM_002256.4	c.417delA	p.Ter139fs	frameshift_variant, stop_lost	Exon 3 of 3	ENST00000367194.5	NP_002247.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KISS1	ENST00000367194.5	c.417delA	p.Ter139fs	frameshift_variant, stop_lost	Exon 3 of 3	1	NM_002256.4	ENSP00000356162.4
REN	ENST00000638118.1	c.-463delA		upstream_gene_variant		5		ENSP00000490307.1

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

GnomAD2 exomes AF: 0.228 AC: 50085 AN: 219744 AF XY: 0.226

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 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

African (AFR) AF: 0.0854 AC: 2840 AN: 33260

American (AMR) AF: 0.279 AC: 12286 AN: 44026

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 5667 AN: 25928

East Asian (EAS) AF: 0.441 AC: 17292 AN: 39200

South Asian (SAS) AF: 0.202 AC: 17074 AN: 84456

European-Finnish (FIN) AF: 0.196 AC: 9834 AN: 50240

Middle Eastern (MID) AF: 0.237 AC: 1098 AN: 4624

European-Non Finnish (NFE) AF: 0.213 AC: 236144 AN: 1108004

Other (OTH) AF: 0.218 AC: 13066 AN: 59806

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

African (AFR) AF: 0.0948 AC: 3913 AN: 41298

American (AMR) AF: 0.242 AC: 3684 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3470

East Asian (EAS) AF: 0.425 AC: 2166 AN: 5092

South Asian (SAS) AF: 0.195 AC: 929 AN: 4766

European-Finnish (FIN) AF: 0.198 AC: 2072 AN: 10468

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.214 AC: 14530 AN: 67818

Other (OTH) AF: 0.203 AC: 426 AN: 2096

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.027
Mutation Taster		=191/9	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: rs71745629; hg19: chr1-204159611; COSMIC: COSV65816897; COSMIC: COSV65816897;