1-204190409-T-TTG

Variant names:

• chr1-204190409-T-TTG
• rs200451423
• NM_002256.4:c.*74_*75insCA

Variant summary

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

The NM_002256.4(KISS1):​c.*74_*75insCA 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 0.13 (1198 hom., cov: 18)
  • Exomes 𝑓: 0.052 (1316 hom.)
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.335
• 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 1-204190409-T-TTG is Benign according to our data. Variant chr1-204190409-T-TTG is described in ClinVar as Benign. ClinVar VariationId is 1258690.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 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.*74_*75insCA		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.*74_*75insCA		3_prime_UTR	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.*74_*75insCA		3_prime_UTR	Exon 2 of 2	ENSP00000552504.1
	REN	ENST00000638118.1	TSL:5	c.-389_-388insCA		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 15525 AN: 121200 Hom.: 1197 Cov.: 18

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.0862

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0454

Gnomad SAS AF: 0.0721

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.0521 AC: 23331 AN: 447486 Hom.: 1316 Cov.: 0 AF XY: 0.0522 AC XY: 12705 AN XY: 243288

African (AFR) AF: 0.133 AC: 1431 AN: 10792

American (AMR) AF: 0.0385 AC: 1088 AN: 28296

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 849 AN: 15604

East Asian (EAS) AF: 0.0166 AC: 383 AN: 23136

South Asian (SAS) AF: 0.0535 AC: 3132 AN: 58488

European-Finnish (FIN) AF: 0.0538 AC: 1300 AN: 24152

Middle Eastern (MID) AF: 0.0600 AC: 109 AN: 1816

European-Non Finnish (NFE) AF: 0.0527 AC: 13781 AN: 261592

Other (OTH) AF: 0.0533 AC: 1258 AN: 23610

GnomAD4 genome AF: 0.128 AC: 15527 AN: 121258 Hom.: 1198 Cov.: 18 AF XY: 0.126 AC XY: 7414 AN XY: 58780

African (AFR) AF: 0.220 AC: 6623 AN: 30170

American (AMR) AF: 0.0860 AC: 1065 AN: 12390

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 326 AN: 2924

East Asian (EAS) AF: 0.0452 AC: 163 AN: 3604

South Asian (SAS) AF: 0.0715 AC: 282 AN: 3946

European-Finnish (FIN) AF: 0.102 AC: 823 AN: 8062

Middle Eastern (MID) AF: 0.109 AC: 27 AN: 248

European-Non Finnish (NFE) AF: 0.103 AC: 5941 AN: 57484

Other (OTH) AF: 0.108 AC: 181 AN: 1674

Alfa AF: 0.0296 Hom.: 38

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		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200451423; hg19: chr1-204159537;