rs201073751

Variant names:

• chr1-204190633-G-A
• rs201073751
• NM_002256.4:c.268C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-204190633-G-A
• chr1-204190633-G-C
• chr1-204190633-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002256.4(KISS1):​c.268C>T​(p.His90Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,432,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H90D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KISS1 NM_002256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0100
• Publications: 15 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028965026).

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.268C>T	p.His90Tyr	missense	Exon 3 of 3	NP_002247.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	ENST00000367194.5	TSL:1 MANE Select	c.268C>T	p.His90Tyr	missense	Exon 3 of 3	ENSP00000356162.4	Q15726
	KISS1	ENST00000882445.1		c.268C>T	p.His90Tyr	missense	Exon 2 of 2	ENSP00000552504.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000579 AC: 11 AN: 190138 AF XY: 0.00000958

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1432402 Hom.: 0 Cov.: 38 AF XY: 0.00000564 AC XY: 4 AN XY: 709830

African (AFR) AF: 0.0000304 AC: 1 AN: 32930

American (AMR) AF: 0.000296 AC: 12 AN: 40518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25500

East Asian (EAS) AF: 0.00 AC: 0 AN: 38342

South Asian (SAS) AF: 0.00 AC: 0 AN: 82702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1097726

Other (OTH) AF: 0.00 AC: 0 AN: 59248

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000171 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000433 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.9
DANN	Benign	0.90
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.010
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.053	T
Polyphen		0.0070	B
Vest4		0.10
MutPred		0.34		Gain of phosphorylation at H90 (P = 0.0409)
MVP		0.043
MPC		0.10
ClinPred		0.013	T
GERP RS		0.087
PromoterAI		0.044	Neutral
Varity_R		0.12
gMVP		0.038
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs201073751; hg19: chr1-204159761;