19-920746-T-C

Position:

• chr19-920746-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_032551.5(KISS1R):​c.1195T>C​(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 0.000000883 in 1,132,048 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: KISS1R NM_032551.5 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.438

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
• PM4: Stoplost variant in NM_032551.5 Downstream stopcodon found after 454 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1R	NM_032551.5	c.1195T>C	p.Ter399Argext*?	stop_lost	5/5	ENST00000234371.10	NP_115940.2
KISS1R	XM_047439545.1	c.1378T>C	p.Ter460Argext*?	stop_lost	4/4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10	c.1195T>C	p.Ter399Argext*?	stop_lost	5/5	1	NM_032551.5	ENSP00000234371.3
KISS1R	ENST00000606939.2	c.*281T>C		splice_region_variant	4/4	5		ENSP00000475639.1
KISS1R	ENST00000606939.2	c.*281T>C		3_prime_UTR_variant	4/4	5		ENSP00000475639.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.83e-7 AC: 1 AN: 1132048 Hom.: 0 Cov.: 32 AF XY: 0.00000185 AC XY: 1 AN XY: 541144

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: 0.00

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	12
DANN	Benign	0.80
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.32	N
Vest4		0.067
GERP RS		2.8

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: rs104894702; hg19: chr19-920746;