chr1-204190474-A-ACCTGCGCCCTCAGCCCCGCC

Position:

• chr1-204190474-A-ACCTGCGCCCTCAGCCCCGCC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002256.4(KISS1):​c.*9_*10insGGCGGGGCTGAGGGCGCAGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,501,544 control chromosomes in the GnomAD database, including 55 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (27 hom., cov: 29)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: KISS1 NM_002256.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.68

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 1-204190474-A-ACCTGCGCCCTCAGCCCCGCC is Benign according to our data. Variant chr1-204190474-A-ACCTGCGCCCTCAGCCCCGCC is described in ClinVar as [Benign]. Clinvar id is 1226970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1466/125460) while in subpopulation AFR AF= 0.0437 (1393/31862). AF 95% confidence interval is 0.0418. There are 27 homozygotes in gnomad4. There are 672 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1	NM_002256.4	c.*9_*10insGGCGGGGCTGAGGGCGCAGG		3_prime_UTR_variant	3/3	ENST00000367194.5	NP_002247.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1	ENST00000367194	c.*9_*10insGGCGGGGCTGAGGGCGCAGG		3_prime_UTR_variant	3/3	1	NM_002256.4	ENSP00000356162.4

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1457 AN: 125406 Hom.: 27 Cov.: 29

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000260

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00385

Gnomad NFE AF: 0.0000832

Gnomad OTH AF: 0.00745

GnomAD3 exomes AF: 0.00193 AC: 375 AN: 194492 Hom.: 3 AF XY: 0.00150 AC XY: 162 AN XY: 107862

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000192

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000617

GnomAD4 exome AF: 0.00114 AC: 1573 AN: 1376084 Hom.: 28 Cov.: 34 AF XY: 0.00100 AC XY: 686 AN XY: 683156

Gnomad4 AFR exome AF: 0.0447

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.0117 AC: 1466 AN: 125460 Hom.: 27 Cov.: 29 AF XY: 0.0111 AC XY: 672 AN XY: 60758

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000261

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000832

Gnomad4 OTH AF: 0.00737

Alfa AF: 0.00467 Hom.: 1

Asia WGS AF: 0.00304 AC: 10 AN: 3306

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 25, 2021

This variant is associated with the following publications: (PMID: 22230814) -

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: rs746113335; hg19: chr1-204159602;