1-204190633-G-C

Position:

• chr1-204190633-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002256.4(KISS1):​c.268C>G​(p.His90Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,584,608 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H90Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 30)
  • Exomes 𝑓: 0.00062 (8 hom.)
• Consequence: KISS1 NM_002256.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0100

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038197935).
• BP6: Variant 1-204190633-G-C is Benign according to our data. Variant chr1-204190633-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 501504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00645 (981/152208) while in subpopulation AFR AF= 0.0223 (928/41522). AF 95% confidence interval is 0.0212. There are 6 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KISS1	NM_002256.4	c.268C>G	p.His90Asp	missense_variant	3/3	ENST00000367194.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KISS1	ENST00000367194.5	c.268C>G	p.His90Asp	missense_variant	3/3	1	NM_002256.4	P1

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 975 AN: 152088 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00137 AC: 260 AN: 190138 Hom.: 1 AF XY: 0.00102 AC XY: 106 AN XY: 104334

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.000963

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000502

Gnomad OTH exome AF: 0.000404

GnomAD4 exome AF: 0.000617 AC: 884 AN: 1432400 Hom.: 8 Cov.: 38 AF XY: 0.000500 AC XY: 355 AN XY: 709828

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000967

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000282

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00645 AC: 981 AN: 152208 Hom.: 6 Cov.: 30 AF XY: 0.00634 AC XY: 472 AN XY: 74412

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.00728

ESP6500AA AF: 0.00908 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00154 AC: 178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2020	This variant is associated with the following publications: (PMID: 33089319, 20237166, 22230814, 21880801) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 18, 2017

- -

Hypogonadotropic hypogonadism 13 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.4
DANN	Benign	0.60
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.19
Sift	Benign	0.071	T;.
Sift4G	Benign	0.10	T;T
Polyphen		0.0030	B;.
Vest4		0.24
MVP		0.068
MPC		0.12
ClinPred		0.0035	T
GERP RS		0.087
Varity_R		0.069
gMVP		0.056

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

LitVar

Other links and lift over

dbSNP: rs201073751; hg19: chr1-204159761;