19-920746-T-C

Variant names:

• chr19-920746-T-C
• rs104894702
• NM_032551.5:c.1195T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 15 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• central precocious puberty 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
KISS1R	NM_032551.5	c.1195T>C	p.Ter399Argext*?	stop_lost	Exon 5 of 5	ENST00000234371.10	NP_115940.2
KISS1R	XM_047439545.1	c.1378T>C	p.Ter460Argext*?	stop_lost	Exon 4 of 4		XP_047295501.1

Ensembl

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

African (AFR) AF: 0.00 AC: 0 AN: 24464

American (AMR) AF: 0.00 AC: 0 AN: 10386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14932

East Asian (EAS) AF: 0.00 AC: 0 AN: 29024

South Asian (SAS) AF: 0.00 AC: 0 AN: 28248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 949288

Other (OTH) AF: 0.0000218 AC: 1 AN: 45958

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		-0.44
Vest4		0.067
GERP RS		2.8
Mutation Taster		=16/184	disease causing

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

Other links and lift over

dbSNP: rs104894702; hg19: chr19-920746;