chr1-204190483-CT-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_002256.4(KISS1):c.417delA(p.Ter139fs) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,600,964 control chromosomes in the GnomAD database, including 39,128 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3189 hom., cov: 23)

Exomes 𝑓: 0.22 ( 35939 hom. )

Consequence

KISS1
NM_002256.4 frameshift, stop_lost

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0270

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

familial juvenile hyperuricemic nephropathy type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
renal tubular dysgenesis of genetic origin
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

REN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4

Stoplost variant in NM_002256.4

BP6

Variant 1-204190483-CT-C is Benign according to our data. Variant chr1-204190483-CT-C is described in ClinVar as Benign. ClinVar VariationId is 403018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 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.417delA	p.Ter139fs	frameshift stop_lost	Exon 3 of 3	NP_002247.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KISS1	ENST00000367194.5	TSL:1 MANE Select	c.417delA	p.Ter139fs	frameshift stop_lost	Exon 3 of 3	ENSP00000356162.4	Q15726
KISS1	ENST00000882445.1		c.417delA	p.Ter139fs	frameshift stop_lost	Exon 2 of 2	ENSP00000552504.1
REN	ENST00000638118.1	TSL:5	c.-463delA		upstream_gene	N/A	ENSP00000490307.1	A0A1B0GUZ2

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28714

AN:

151302

Hom.:

3186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0949

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.425

Gnomad SAS

AF:

0.195

Gnomad FIN

AF:

0.198

Gnomad MID

AF:

0.245

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.201

GnomAD2 exomes

AF:

0.228

AC:

50085

AN:

219744

AF XY:

0.226

show subpopulations

Gnomad AFR exome

AF:

0.0860

Gnomad AMR exome

AF:

0.283

Gnomad ASJ exome

AF:

0.214

Gnomad EAS exome

AF:

0.411

Gnomad FIN exome

AF:

0.194

Gnomad NFE exome

AF:

0.210

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.218

AC:

315301

AN:

1449544

Hom.:

35939

Cov.:

AF XY:

0.217

AC XY:

156309

AN XY:

720374

show subpopulations

African (AFR)

AF:

0.0854

AC:

2840

AN:

33260

American (AMR)

AF:

0.279

AC:

12286

AN:

44026

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

5667

AN:

25928

East Asian (EAS)

AF:

0.441

AC:

17292

AN:

39200

South Asian (SAS)

AF:

0.202

AC:

17074

AN:

84456

European-Finnish (FIN)

AF:

0.196

AC:

9834

AN:

50240

Middle Eastern (MID)

AF:

0.237

AC:

1098

AN:

4624

European-Non Finnish (NFE)

AF:

0.213

AC:

236144

AN:

1108004

Other (OTH)

AF:

0.218

AC:

13066

AN:

59806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

12405

24810

37214

49619

62024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8300

16600

24900

33200

41500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.190

AC:

28730

AN:

151420

Hom.:

3189

Cov.:

AF XY:

0.191

AC XY:

14141

AN XY:

73964

show subpopulations

African (AFR)

AF:

0.0948

AC:

3913

AN:

41298

American (AMR)

AF:

0.242

AC:

3684

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

748

AN:

3470

East Asian (EAS)

AF:

0.425

AC:

2166

AN:

5092

South Asian (SAS)

AF:

0.195

AC:

929

AN:

4766

European-Finnish (FIN)

AF:

0.198

AC:

2072

AN:

10468

Middle Eastern (MID)

AF:

0.264

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.214

AC:

14530

AN:

67818

Other (OTH)

AF:

0.203

AC:

426

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

984

1968

2953

3937

4921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

312

624

936

1248

1560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.132

Hom.:

299

Bravo

AF:

0.191

Asia WGS

AF:

0.275

AC:

953

AN:

3470

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hypogonadotropic hypogonadism 13 with or without anosmia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.027

Mutation Taster

=191/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over