chr19-917740-T-C

Position:

• chr19-917740-T-C

Variant summary

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

The NM_032551.5(KISS1R):​c.238T>C​(p.Tyr80His) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,604,188 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 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.92

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, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KISS1R	NM_032551.5	c.238T>C	p.Tyr80His	missense_variant	1/5	ENST00000234371.10
KISS1R	XM_047439545.1	c.238T>C	p.Tyr80His	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KISS1R	ENST00000234371.10	c.238T>C	p.Tyr80His	missense_variant	1/5	1	NM_032551.5	P1
KISS1R	ENST00000606939.2	c.238T>C	p.Tyr80His	missense_variant	1/4	5
KISS1R	ENST00000592648.1	c.238T>C	p.Tyr80His	missense_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1451978 Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 4 AN XY: 721412

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: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.238T>C (p.Y80H) alteration is located in exon 1 (coding exon 1) of the KISS1R gene. This alteration results from a T to C substitution at nucleotide position 238, causing the tyrosine (Y) at amino acid position 80 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with KISS1R-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 80 of the KISS1R protein (p.Tyr80His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.0	.;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.2	.;D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.64, 0.64
MutPred		0.78		Loss of stability (P = 0.1203);Loss of stability (P = 0.1203);Loss of stability (P = 0.1203);
MVP		0.98
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.93
gMVP		0.52

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: rs1047587176; hg19: chr19-917740;