Genetic Variant KISS1R:p.Asn78Thr (chr19-917735-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032551.5(KISS1R):c.233A>C(p.Asn78Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,454,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N78S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KISS1R
NM_032551.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.06

Publications

0 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: 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

KISS1R links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

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.233A>C	p.Asn78Thr	missense	Exon 1 of 5	NP_115940.2	Q969F8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KISS1R	ENST00000234371.10	TSL:1 MANE Select	c.233A>C	p.Asn78Thr	missense	Exon 1 of 5	ENSP00000234371.3	Q969F8
KISS1R	ENST00000909146.1		c.233A>C	p.Asn78Thr	missense	Exon 1 of 5	ENSP00000579205.1
KISS1R	ENST00000606939.2	TSL:5	c.233A>C	p.Asn78Thr	missense	Exon 1 of 4	ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722796

show subpopulations

African (AFR)

AF:

0.0000301

AC:

AN:

33202

American (AMR)

AF:

0.00

AC:

AN:

44244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39348

South Asian (SAS)

AF:

0.00

AC:

AN:

85576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108664

Other (OTH)

AF:

0.00

AC:

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

0.0063

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.7

PhyloP100

7.1

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.45

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.70

MutPred

0.93

Gain of glycosylation at N78 (P = 0.0151)

MVP

0.92

MPC

1.1

ClinPred

0.99

GERP RS

3.9

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.96

gMVP

0.52

Mutation Taster

=39/61

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over