rs4951319

Variant names:

• chr1-204193102-T-C
• rs4951319
• NM_002256.4:c.-38-188A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002256.4(KISS1):​c.-38-188A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 151,916 control chromosomes in the GnomAD database, including 6,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (6779 hom., cov: 32)
• Consequence: KISS1 NM_002256.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0730
• Publications: 7 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]

KISS1 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypogonadotropic hypogonadism 13 with or without anosmia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-204193102-T-C is Benign according to our data. Variant chr1-204193102-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251415.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1	NM_002256.4	c.-38-188A>G		intron_variant	Intron 1 of 2	ENST00000367194.5	NP_002247.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KISS1	ENST00000367194.5	c.-38-188A>G		intron_variant	Intron 1 of 2	1	NM_002256.4	ENSP00000356162.4

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44329 AN: 151798 Hom.: 6771 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.285

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.292 AC: 44374 AN: 151916 Hom.: 6779 Cov.: 32 AF XY: 0.291 AC XY: 21573 AN XY: 74246

African (AFR) AF: 0.356 AC: 14744 AN: 41418

American (AMR) AF: 0.318 AC: 4848 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3466

East Asian (EAS) AF: 0.436 AC: 2245 AN: 5154

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4814

European-Finnish (FIN) AF: 0.221 AC: 2337 AN: 10556

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17124 AN: 67936

Other (OTH) AF: 0.286 AC: 604 AN: 2112

Alfa AF: 0.275 Hom.: 1004

Bravo AF: 0.303

Asia WGS AF: 0.320 AC: 1113 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.2
DANN	Benign	0.81
PhyloP100		-0.073
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4951319; hg19: chr1-204162230;