chr1-204190409-T-TGCCC

Variant names:

• chr1-204190409-T-TGCCC
• rs200451423
• NM_002256.4:c.*74_*75insGGGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002256.4(KISS1):​c.*74_*75insGGGC 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: 0.00059 (3 hom.)
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1	NM_002256.4	c.*74_*75insGGGC		3_prime_UTR_variant	Exon 3 of 3	ENST00000367194.5	NP_002247.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KISS1	ENST00000367194	c.*74_*75insGGGC		3_prime_UTR_variant	Exon 3 of 3	1	NM_002256.4	ENSP00000356162.4
REN	ENST00000638118.1	c.-389_-388insGGGC		upstream_gene_variant		5		ENSP00000490307.1

Frequencies

GnomAD3 genomes AF: 0.00000823 AC: 1 AN: 121440 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.0000332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.000590 AC: 266 AN: 450498 Hom.: 3 Cov.: 0 AF XY: 0.000564 AC XY: 138 AN XY: 244896

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.000317

Gnomad4 ASJ exome AF: 0.000254

Gnomad4 EAS exome AF: 0.00104

Gnomad4 SAS exome AF: 0.0000341

Gnomad4 FIN exome AF: 0.000327

Gnomad4 NFE exome AF: 0.000694

Gnomad4 OTH exome AF: 0.000757

GnomAD4 genome AF: 0.00000823 AC: 1 AN: 121498 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 58910

Gnomad4 AFR AF: 0.0000331

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200451423; hg19: chr1-204159537;