rs104894703

Variant names:

• chr19-918604-T-C
• rs104894703
• NM_032551.5:c.305T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3 PP3 PP5_Very_Strong BS1_Supporting

The NM_032551.5(KISS1R):​c.305T>C​(p.Leu102Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000129 in 1,551,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002013329: Published functional studies demonstrate a damaging effect on the function of the KISSR1 receptor protein" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L102L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.05
• Publications: 19 publications found

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]

KISS1R Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 8 with or without anosmia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• central precocious puberty 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002013329: Published functional studies demonstrate a damaging effect on the function of the KISSR1 receptor protein; PMID:12944565, PMID:17164310, PMID:25147978, PMID:31589614, PMID:30205368, PMID:31885997, PMID:20816945, PMID:23349759
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• PP5: Variant 19-918604-T-C is Pathogenic according to our data. Variant chr19-918604-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000129 (18/1399394) while in subpopulation MID AF = 0.00106 (6/5682). AF 95% confidence interval is 0.000459. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032551.5. 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
	KISS1R	NM_032551.5	MANE Select	c.305T>C	p.Leu102Pro	missense	Exon 2 of 5	NP_115940.2	Q969F8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1R	ENST00000234371.10	TSL:1 MANE Select	c.305T>C	p.Leu102Pro	missense	Exon 2 of 5	ENSP00000234371.3	Q969F8
	KISS1R	ENST00000909146.1		c.305T>C	p.Leu102Pro	missense	Exon 2 of 5	ENSP00000579205.1
	KISS1R	ENST00000606939.2	TSL:5	c.305T>C	p.Leu102Pro	missense	Exon 2 of 4	ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000255 AC: 4 AN: 156912 AF XY: 0.0000121

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.0000403

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000331

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1399394 Hom.: 0 Cov.: 34 AF XY: 0.0000145 AC XY: 10 AN XY: 690388

African (AFR) AF: 0.0000316 AC: 1 AN: 31678

American (AMR) AF: 0.0000280 AC: 1 AN: 35778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 35906

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48594

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5682

European-Non Finnish (NFE) AF: 0.00000741 AC: 8 AN: 1079256

Other (OTH) AF: 0.0000172 AC: 1 AN: 58018

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000309 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Central precocious puberty 1 (1)
1	-	-	Hypogonadotropic hypogonadism 8 with or without anosmia (1)
1	-	-	Hypogonadotropic hypogonadism 8 without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.26
Sift	Benign	0.041	D
Sift4G	Benign	0.12	T
Polyphen		0.95	P
Vest4		0.80
MVP		0.82
MPC		2.5
ClinPred		0.98	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.67
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs104894703; hg19: chr19-918604;