1-204190416-C-CA

Variant names:

• chr1-204190416-C-CA
• rs35128240
• NM_002256.4:c.*67_*68insT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002256.4(KISS1):​c.*67_*68insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (2657 hom., cov: 22)
  • Exomes 𝑓: 0.14 (6029 hom.)
  • Failed GnomAD Quality Control
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• Publications: 2 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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal tubular dysgenesis of genetic origin

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 1-204190416-C-CA is Benign according to our data. Variant chr1-204190416-C-CA is described in ClinVar as Benign. ClinVar VariationId is 1225438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6029 AR,AD gene

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.*67_*68insT		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.*67_*68insT		3_prime_UTR	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.*67_*68insT		3_prime_UTR	Exon 2 of 2	ENSP00000552504.1
	REN	ENST00000638118.1	TSL:5	c.-396_-395insT		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 29358 AN: 144584 Hom.: 2650 Cov.: 22

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.144 AC: 64237 AN: 444726 Hom.: 6029 Cov.: 3 AF XY: 0.146 AC XY: 35196 AN XY: 241792

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.122 AC: 1348 AN: 11068

American (AMR) AF: 0.180 AC: 4811 AN: 26714

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 1991 AN: 15544

East Asian (EAS) AF: 0.261 AC: 5708 AN: 21890

South Asian (SAS) AF: 0.170 AC: 9785 AN: 57696

European-Finnish (FIN) AF: 0.115 AC: 2872 AN: 25030

Middle Eastern (MID) AF: 0.141 AC: 255 AN: 1810

European-Non Finnish (NFE) AF: 0.131 AC: 34264 AN: 261408

Other (OTH) AF: 0.136 AC: 3203 AN: 23566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.203 AC: 29390 AN: 144676 Hom.: 2657 Cov.: 22 AF XY: 0.203 AC XY: 14339 AN XY: 70468

African (AFR) AF: 0.173 AC: 6725 AN: 38876

American (AMR) AF: 0.238 AC: 3487 AN: 14664

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 685 AN: 3354

East Asian (EAS) AF: 0.387 AC: 1835 AN: 4736

South Asian (SAS) AF: 0.179 AC: 817 AN: 4556

European-Finnish (FIN) AF: 0.189 AC: 1805 AN: 9566

Middle Eastern (MID) AF: 0.267 AC: 77 AN: 288

European-Non Finnish (NFE) AF: 0.203 AC: 13372 AN: 65750

Other (OTH) AF: 0.210 AC: 422 AN: 2008

Alfa AF: 0.0697 Hom.: 104

Asia WGS AF: 0.261 AC: 889 AN: 3420

ClinVar

ClinVar submissions as Germline

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

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: rs35128240; hg19: chr1-204159544; COSMIC: COSV65816948; COSMIC: COSV65816948;