Genetic Variant NM_002256.4:c.*74_*75insGCA (chr1-204190409-T-TTGC) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_002256.4(KISS1):c.*74_*75insGCA 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 0.000074 ( 0 hom., cov: 18)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

KISS1
NM_002256.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.335

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 Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1	NM_002256.4 link	c.74_75insGCA		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.74_75insGCA		3_prime_UTR_variant	Exon 3 of 3	1	NM_002256.4	ENSP00000356162.4		Q15726
REN	ENST00000638118.1 link	c.-389_-388insGCA		upstream_gene_variant		5		ENSP00000490307.1		A0A1B0GUZ2

Frequencies

GnomAD3 genomes

AF:

0.0000741

AC:

AN:

121444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000664

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000161

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000755

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000347

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000279

AC:

126

AN:

451702

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

AN XY:

245468

show subpopulations

Gnomad4 AFR exome

AF:

0.00110

Gnomad4 AMR exome

AF:

0.000458

Gnomad4 ASJ exome

AF:

0.000507

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000307

Gnomad4 FIN exome

AF:

0.000204

Gnomad4 NFE exome

AF:

0.000250

Gnomad4 OTH exome

AF:

0.000126

GnomAD4 genome

AF:

0.0000741

AC:

AN:

121502

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

58916

show subpopulations

Gnomad4 AFR

AF:

0.0000662

Gnomad4 AMR

AF:

0.000161

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000756

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000347

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

NM_002256.4:c.74_75insGCA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over