chr19-917735-A-G

Position:

• chr19-917735-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032551.5(KISS1R):​c.233A>G​(p.Asn78Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,606,524 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.06

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KISS1R	NM_032551.5	c.233A>G	p.Asn78Ser	missense_variant	1/5	ENST00000234371.10
KISS1R	XM_047439545.1	c.233A>G	p.Asn78Ser	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KISS1R	ENST00000234371.10	c.233A>G	p.Asn78Ser	missense_variant	1/5	1	NM_032551.5	P1
KISS1R	ENST00000606939.2	c.233A>G	p.Asn78Ser	missense_variant	1/4	5
KISS1R	ENST00000592648.1	c.233A>G	p.Asn78Ser	missense_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000129 AC: 3 AN: 232844 Hom.: 0 AF XY: 0.0000157 AC XY: 2 AN XY: 127422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000981

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1454216 Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11 AN XY: 722796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000166 AC: 2

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

Illumina Laboratory Services, Illumina

May 15, 2018

The KISS1R c.233A>G p.(Asn78Ser) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in trans with a pathogenic variant in the proband with a phenotype consistent with hypogonadotropic hypogonadism 8 with or without anosmia. Based on the limited evidence, the c.233A>G p.(Asn78Ser) variant is classified as a variant of uncertain significance for hypogonadotropic hypogonadism 8 with or without anosmia. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.1	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.1	.;D;.
REVEL	Uncertain	0.38
Sift	Benign	0.049	.;D;.
Sift4G	Uncertain	0.053	T;D;D
Polyphen		0.99	.;D;.
Vest4		0.31, 0.39
MutPred		0.96		Gain of glycosylation at N78 (P = 0.1294);Gain of glycosylation at N78 (P = 0.1294);Gain of glycosylation at N78 (P = 0.1294);
MVP		0.91
MPC		1.3
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.71
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs540538484; hg19: chr19-917735;