NM_002256.4:c.*74_*75insGGC

Variant names:

• chr1-204190409-T-TGCC
• rs200451423
• NM_002256.4:c.*74_*75insGGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002256.4(KISS1):​c.*74_*75insGGC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000082 (0 hom., cov: 18)
  • Exomes 𝑓: 0.000093 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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_*75insGGC		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_*75insGGC		3_prime_UTR	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.*74_*75insGGC		3_prime_UTR	Exon 2 of 2	ENSP00000552504.1
	REN	ENST00000638118.1	TSL:5	c.-389_-388insGGC		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes AF: 0.00000823 AC: 1 AN: 121446 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000276

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000930 AC: 42 AN: 451548 Hom.: 0 Cov.: 0 AF XY: 0.0000815 AC XY: 20 AN XY: 245384

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

African (AFR) AF: 0.000276 AC: 3 AN: 10882

American (AMR) AF: 0.0000704 AC: 2 AN: 28390

Ashkenazi Jewish (ASJ) AF: 0.000190 AC: 3 AN: 15776

East Asian (EAS) AF: 0.000129 AC: 3 AN: 23248

South Asian (SAS) AF: 0.00 AC: 0 AN: 58642

European-Finnish (FIN) AF: 0.0000815 AC: 2 AN: 24546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1832

European-Non Finnish (NFE) AF: 0.000106 AC: 28 AN: 264356

Other (OTH) AF: 0.0000419 AC: 1 AN: 23876

⚠️ 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: 0.00000823 AC: 1 AN: 121506 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 58916

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

African (AFR) AF: 0.00 AC: 0 AN: 30222

American (AMR) AF: 0.00 AC: 0 AN: 12410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2924

East Asian (EAS) AF: 0.000277 AC: 1 AN: 3612

South Asian (SAS) AF: 0.00 AC: 0 AN: 3966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57594

Other (OTH) AF: 0.00 AC: 0 AN: 1674

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.34

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;