Genetic Variant KISS1:c.*67_*68insT (chr1-204190416-C-CA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBA1

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

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00

Variant links:

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]

KISS1 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 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 id is 1225438.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1	NM_002256.4 link	c.67_68insT		3_prime_UTR_variant	Exon 3 of 3	ENST00000367194.5	NP_002247.3	Q15726

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KISS1	ENST00000367194 link	c.67_68insT		3_prime_UTR_variant	Exon 3 of 3	1	NM_002256.4	ENSP00000356162.4		Q15726
REN	ENST00000638118.1 link	c.-396_-395insT		upstream_gene_variant		5		ENSP00000490307.1		A0A1B0GUZ2

Frequencies

GnomAD3 genomes

AF:

0.203

AC:

29358

AN:

144584

Hom.:

2650

Cov.:

show subpopulations

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.:

AF XY:

0.146

AC XY:

35196

AN XY:

241792

show subpopulations

Gnomad4 AFR exome

AF:

0.122

Gnomad4 AMR exome

AF:

0.180

Gnomad4 ASJ exome

AF:

0.128

Gnomad4 EAS exome

AF:

0.261

Gnomad4 SAS exome

AF:

0.170

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.131

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.203

AC:

29390

AN:

144676

Hom.:

2657

Cov.:

AF XY:

0.203

AC XY:

14339

AN XY:

70468

show subpopulations

Gnomad4 AFR

AF:

0.173

Gnomad4 AMR

AF:

0.238

Gnomad4 ASJ

AF:

0.204

Gnomad4 EAS

AF:

0.387

Gnomad4 SAS

AF:

0.179

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.203

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.0697

Hom.:

104

Asia WGS

AF:

0.261

AC:

889

AN:

3420

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over