rs28939719

Variant names:

• chr19-919563-T-C
• rs28939719
• NM_032551.5:c.443T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_032551.5(KISS1R):​c.443T>C​(p.Leu148Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,560 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.05
• Publications: 21 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 19-919563-T-C is Pathogenic according to our data. Variant chr19-919563-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5755.Status of the report is no_assertion_criteria_provided, 0 stars.

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.443T>C	p.Leu148Ser	missense	Exon 3 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.443T>C	p.Leu148Ser	missense	Exon 3 of 5	ENSP00000234371.3	Q969F8
	KISS1R	ENST00000909146.1		c.443T>C	p.Leu148Ser	missense	Exon 3 of 5	ENSP00000579205.1
	KISS1R	ENST00000606939.2	TSL:5	c.443T>C	p.Leu148Ser	missense	Exon 3 of 4	ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 165772 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000142 AC: 2 AN: 1405560 Hom.: 0 Cov.: 33 AF XY: 0.00000288 AC XY: 2 AN XY: 695118

African (AFR) AF: 0.00 AC: 0 AN: 32378

American (AMR) AF: 0.00 AC: 0 AN: 37356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25274

East Asian (EAS) AF: 0.00 AC: 0 AN: 37038

South Asian (SAS) AF: 0.00 AC: 0 AN: 80340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1086982

Other (OTH) AF: 0.00 AC: 0 AN: 58460

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hypogonadotropic hypogonadism 8 without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.92		Gain of glycosylation at L148 (P = 0.0075)
MVP		0.92
MPC		2.3
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.88
gMVP		0.62
Mutation Taster		=8/92	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: rs28939719; hg19: chr19-919563;