NM_002256.4:c.*73G>C

Variant names:

• chr1-204190411-C-G
• rs540653478
• NM_002256.4:c.*73G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002256.4(KISS1):​c.*73G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 537,206 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (73 hom., cov: 28)
  • Exomes 𝑓: 0.0016 (92 hom.)
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.423
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-204190411-C-G is Benign according to our data. Variant chr1-204190411-C-G is described in ClinVar as Benign. ClinVar VariationId is 1267581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0539 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.*73G>C		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.*73G>C		3_prime_UTR	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.*73G>C		3_prime_UTR	Exon 2 of 2	ENSP00000552504.1
	REN	ENST00000638118.1	TSL:5	c.-390G>C		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 1520 AN: 113604 Hom.: 72 Cov.: 28

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00443

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00775

Gnomad NFE AF: 0.000128

Gnomad OTH AF: 0.0118

GnomAD4 exome AF: 0.00160 AC: 679 AN: 423532 Hom.: 92 Cov.: 0 AF XY: 0.00117 AC XY: 271 AN XY: 231214

African (AFR) AF: 0.0578 AC: 535 AN: 9252

American (AMR) AF: 0.00226 AC: 58 AN: 25716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14674

East Asian (EAS) AF: 0.00 AC: 0 AN: 23138

South Asian (SAS) AF: 0.000139 AC: 8 AN: 57348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23222

Middle Eastern (MID) AF: 0.00358 AC: 6 AN: 1678

European-Non Finnish (NFE) AF: 0.0000366 AC: 9 AN: 246172

Other (OTH) AF: 0.00282 AC: 63 AN: 22332

GnomAD4 genome AF: 0.0135 AC: 1540 AN: 113674 Hom.: 73 Cov.: 28 AF XY: 0.0134 AC XY: 745 AN XY: 55396

African (AFR) AF: 0.0563 AC: 1458 AN: 25916

American (AMR) AF: 0.00443 AC: 54 AN: 12200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2698

East Asian (EAS) AF: 0.00 AC: 0 AN: 3760

South Asian (SAS) AF: 0.00 AC: 0 AN: 3890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8020

Middle Eastern (MID) AF: 0.00847 AC: 2 AN: 236

European-Non Finnish (NFE) AF: 0.000128 AC: 7 AN: 54598

Other (OTH) AF: 0.0117 AC: 19 AN: 1630

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.0264

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.45
PhyloP100		-0.42
PromoterAI		0.019	Neutral
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: rs540653478; hg19: chr1-204159539;