chr1-204191898-A-G

Variant names:

• chr1-204191898-A-G
• rs7538038
• NM_002256.4:c.103+876T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002256.4(KISS1):​c.103+876T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,072 control chromosomes in the GnomAD database, including 6,736 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6736 hom., cov: 32)
• Consequence: KISS1 NM_002256.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.392
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	NM_002256.4	MANE Select	c.103+876T>C		intron	N/A	NP_002247.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1	ENST00000367194.5	TSL:1 MANE Select	c.103+876T>C		intron	N/A	ENSP00000356162.4

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44185 AN: 151954 Hom.: 6728 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.291 AC: 44230 AN: 152072 Hom.: 6736 Cov.: 32 AF XY: 0.289 AC XY: 21514 AN XY: 74346

African (AFR) AF: 0.353 AC: 14658 AN: 41478

American (AMR) AF: 0.317 AC: 4837 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3470

East Asian (EAS) AF: 0.432 AC: 2232 AN: 5166

South Asian (SAS) AF: 0.233 AC: 1125 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2342 AN: 10592

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

European-Non Finnish (NFE) AF: 0.251 AC: 17086 AN: 67958

Other (OTH) AF: 0.287 AC: 606 AN: 2112

Alfa AF: 0.268 Hom.: 940

Bravo AF: 0.302

Asia WGS AF: 0.322 AC: 1119 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.52
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs7538038; hg19: chr1-204161026;