chr19-920746-T-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_032551.5(KISS1R):c.1195T>A(p.Ter399Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,284,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

KISS1R
NM_032551.5 stop_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.438

Publications

15 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: Pathogenic. The variant received 10 ACMG points.

PM4

Stoplost variant in NM_032551.5 Downstream stopcodon found after 454 codons.

PP5

Variant 19-920746-T-A is Pathogenic according to our data. Variant chr19-920746-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KISS1R	NM_032551.5 link	c.1195T>A	p.Ter399Argext*?	stop_lost	Exon 5 of 5	ENST00000234371.10	NP_115940.2	Q969F8
KISS1R	XM_047439545.1 link	c.1378T>A	p.Ter460Argext*?	stop_lost	Exon 4 of 4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KISS1R	ENST00000234371.10 link	c.1195T>A	p.Ter399Argext*?	stop_lost	Exon 5 of 5	1	NM_032551.5	ENSP00000234371.3	Q969F8
KISS1R	ENST00000606939.2 link	c.*281T>A		splice_region_variant	Exon 4 of 4	5		ENSP00000475639.1	U3KQ86
KISS1R	ENST00000606939.2 link	c.*281T>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000681

AC:

AN:

29374

AF XY:

0.0000606

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:

0.000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000654

AC:

AN:

1132048

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

541144

show subpopulations

African (AFR)

AF:

0.000123

AC:

AN:

24464

American (AMR)

AF:

0.00

AC:

AN:

10386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14932

East Asian (EAS)

AF:

0.00

AC:

AN:

29024

South Asian (SAS)

AF:

0.00

AC:

AN:

28248

European-Finnish (FIN)

AF:

0.000319

AC:

AN:

25094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4654

European-Non Finnish (NFE)

AF:

0.0000632

AC:

AN:

949288

Other (OTH)

AF:

0.0000653

AC:

AN:

45958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000106

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000464

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change disrupts the translational stop signal of the KISS1R mRNA. It is expected to extend the length of the KISS1R protein by an uncertain number of additional amino acid residues. 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 protein extension has been observed in individuals with hypogonadotropic hypogonadism (PMID: 14573733, 23349759, 31073722). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5757). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects KISS1R function (PMID: 14573733). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jan 30, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Stop codon loss and change to an arginine codon, leading to protein extension and the addition of an unknown number of amino acids at the C-terminus, and other similar variants have been reported in HGMD; Published functional studies suggest a damaging effect on ligand-induced inositol production and mRNA stability (PMID: 14573733); This variant is associated with the following publications: (PMID: 30205368, 34970798, 27094476, 20816945, 30339828, 16757106, 23349759, 14573733, 31073722, 26510589) -

KISS1R-related disorder

Pathogenic:1

Oct 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KISS1R c.1195T>A variant is predicted to result in extension of the open reading frame (p.*399Argext*89). This variant is predicted to disrupt the translation stop signal and result in protein extension. This variant was reported in the homozygous or compound heterozygous state in individuals with hypogonadotropic hypogonadism (Seminara. 2003. PubMed ID: 14573733; Brioude. 2013. PubMed ID: 23349759; Moalla. 2019. PubMed ID: 31073722). This variant is reported in 0.018% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-920746-T-A). This variant is interpreted as likely pathogenic. -

Hypogonadotropic hypogonadism 8 without anosmia

Pathogenic:1

Jan 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hypogonadotropic hypogonadism

Pathogenic:1

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.89

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.47

PhyloP100

-0.44

Vest4

0.067

GERP RS

2.8

Mutation Taster

=16/184

disease causing (ClinVar)

(source)

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

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