19-917584-A-C

Position:

• chr19-917584-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_032551.5(KISS1R):​c.82A>C​(p.Asn28His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,387,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity KISSR_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3168694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1R	NM_032551.5	c.82A>C	p.Asn28His	missense_variant	1/5	ENST00000234371.10	NP_115940.2
KISS1R	XM_047439545.1	c.82A>C	p.Asn28His	missense_variant	1/4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10	c.82A>C	p.Asn28His	missense_variant	1/5	1	NM_032551.5	ENSP00000234371.3
KISS1R	ENST00000606939.2	c.82A>C	p.Asn28His	missense_variant	1/4	5		ENSP00000475639.1
KISS1R	ENST00000592648.1	c.82A>C	p.Asn28His	missense_variant	1/2	5		ENSP00000467666.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1387696 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 684712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 8 with or without anosmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.N28H in KISS1R (NM_032551.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.N28H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. Insilico tools predict the varian to be damaging but the residue is not conserved across species. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	.;T;.
Eigen	Benign	-0.097
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	.;N;.
REVEL	Benign	0.13
Sift	Benign	0.045	.;D;.
Sift4G	Uncertain	0.038	D;T;T
Polyphen		0.98	.;D;.
Vest4		0.31, 0.34
MutPred		0.21		Gain of phosphorylation at S30 (P = 0.1656);Gain of phosphorylation at S30 (P = 0.1656);Gain of phosphorylation at S30 (P = 0.1656);
MVP		0.91
MPC		1.8
ClinPred		0.65	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-917584;