rs73507527

Positions:

• chr19-919933-G-A
• chr19-919933-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032551.5(KISS1R):​c.565G>A​(p.Ala189Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,564,126 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (78 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.74

Genes affected

KISS1R (HGNC:4510): (KISS1 receptor) The protein encoded by this gene is a galanin-like G protein-coupled receptor that binds metastin, a peptide encoded by the metastasis suppressor gene KISS1. The tissue distribution of the expressed gene suggests that it is involved in the regulation of endocrine function, and this is supported by the finding that this gene appears to play a role in the onset of puberty. Mutations in this gene have been associated with hypogonadotropic hypogonadism and central precocious puberty. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017435253).
• BP6: Variant 19-919933-G-A is Benign according to our data. Variant chr19-919933-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1R	NM_032551.5	c.565G>A	p.Ala189Thr	missense_variant	4/5	ENST00000234371.10	NP_115940.2
KISS1R	XM_047439545.1	c.565G>A	p.Ala189Thr	missense_variant	4/4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10	c.565G>A	p.Ala189Thr	missense_variant	4/5	1	NM_032551.5	ENSP00000234371	P1
KISS1R	ENST00000606939.2	c.505+308G>A		intron_variant		5		ENSP00000475639

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2717 AN: 152122 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00456 AC: 756 AN: 165870 Hom.: 20 AF XY: 0.00380 AC XY: 349 AN XY: 91732

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00249 AC: 3510 AN: 1411886 Hom.: 78 Cov.: 33 AF XY: 0.00227 AC XY: 1584 AN XY: 699166

Gnomad4 AFR exome AF: 0.0628

Gnomad4 AMR exome AF: 0.00345

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.000241

Gnomad4 NFE exome AF: 0.000929

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.0179 AC: 2725 AN: 152240 Hom.: 73 Cov.: 33 AF XY: 0.0174 AC XY: 1299 AN XY: 74468

Gnomad4 AFR AF: 0.0600

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00509 Hom.: 3

Bravo AF: 0.0202

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0428 AC: 176

ESP6500EA AF: 0.00163 AC: 13

ExAC AF: 0.00404 AC: 464

Asia WGS AF: 0.00491 AC: 18 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.92
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.034
MVP		0.39
MPC		0.86
ClinPred		0.0015	T
GERP RS		2.5
Varity_R		0.054
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs73507527; hg19: chr19-919933;