chr19-920718-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_ModerateBS1_Supporting

The NM_032551.5(KISS1R):c.1167C>A(p.Cys389*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,304,108 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

KISS1R
NM_032551.5 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -4.12

Publications

2 publications found

Variant links:

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

KISS1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0251 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000381 (58/152304) while in subpopulation NFE AF = 0.000706 (48/68018). AF 95% confidence interval is 0.000547. There are 1 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1R	NM_032551.5 link	c.1167C>A	p.Cys389*	stop_gained	Exon 5 of 5	ENST00000234371.10	NP_115940.2	Q969F8
KISS1R	XM_047439545.1 link	c.1350C>A	p.Cys450*	stop_gained	Exon 4 of 4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10 link	c.1167C>A	p.Cys389*	stop_gained	Exon 5 of 5	1	NM_032551.5	ENSP00000234371.3		Q969F8
KISS1R	ENST00000606939.2 link	c.*253C>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000475639.1		U3KQ86

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000355

AC:

AN:

33798

AF XY:

0.000311

show subpopulations

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:

0.000481

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000399

AC:

460

AN:

1151804

Hom.:

Cov.:

AF XY:

0.000440

AC XY:

244

AN XY:

554058

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24744

American (AMR)

AF:

0.0000855

AC:

AN:

11690

Ashkenazi Jewish (ASJ)

AF:

0.0000630

AC:

AN:

15878

East Asian (EAS)

AF:

0.00

AC:

AN:

29160

South Asian (SAS)

AF:

0.000813

AC:

AN:

31984

European-Finnish (FIN)

AF:

0.0000382

AC:

AN:

26172

Middle Eastern (MID)

AF:

0.000421

AC:

AN:

4754

European-Non Finnish (NFE)

AF:

0.000435

AC:

418

AN:

960380

Other (OTH)

AF:

0.000234

AC:

AN:

47042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000381

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41578

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000133

AC:

ExAC

AF:

0.000184

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Aug 10, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KISS1R c.1167C>A (p.Cys389X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. This variant was predicted as not involved in nonsense mediated decay. The variant allele was found at a frequency of 0.00034 in 34898 control chromosomes (gnomAD). c.1167C>A has been reported in the literature in individuals affected with Hypogonadotropic Hypogonadism (Shaw_2011, Knskoski_2014, Cangiano_2019). These reports do not provide unequivocal conclusions about association of the variant with Hypogonadotropic Hypogonadism 8 With Or Without Anosmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30669598, 24522099, 21209029, 21704672). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:2

Jun 12, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in two individuals with normosmic hypogonadotropic hypogonadism; however, neither individual was reported to have a second KISS1R variant and it is unclear whether the presence of variants in other genes associated with hypogonadotropic hypogonadism was excluded (Shaw et al., 2011; Kansakoski et al., 2014); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 24522099, 21209029) -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Cys389*) in the KISS1R gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the KISS1R protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with KISS1R-related conditions (PMID: 21209029, 24522099). This variant is also known as GPR54 C389X. ClinVar contains an entry for this variant (Variation ID: 435653). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Benign

0.95

Eigen

Benign

-0.68

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.023

PhyloP100

-4.1

Vest4

0.69

GERP RS

-6.3

Mutation Taster

=54/146

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over