19-920708-G-T

Variant names:

• chr19-920708-G-T
• rs121908499
• NM_032551.5:c.1157G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032551.5(KISS1R):​c.1157G>T​(p.Arg386Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000867 in 1,153,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11052033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032551.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1R	NM_032551.5	MANE Select	c.1157G>T	p.Arg386Leu	missense	Exon 5 of 5	NP_115940.2	Q969F8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1R	ENST00000234371.10	TSL:1 MANE Select	c.1157G>T	p.Arg386Leu	missense	Exon 5 of 5	ENSP00000234371.3	Q969F8
	KISS1R	ENST00000909146.1		c.1151G>T	p.Arg384Leu	missense	Exon 5 of 5	ENSP00000579205.1
	KISS1R	ENST00000606939.2	TSL:5	c.*243G>T		3_prime_UTR	Exon 4 of 4	ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.67e-7 AC: 1 AN: 1153792 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 555298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24820

American (AMR) AF: 0.00 AC: 0 AN: 12260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16258

East Asian (EAS) AF: 0.00 AC: 0 AN: 28994

South Asian (SAS) AF: 0.00 AC: 0 AN: 32812

European-Finnish (FIN) AF: 0.0000382 AC: 1 AN: 26200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 960566

Other (OTH) AF: 0.00 AC: 0 AN: 47126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.026
Sift	Benign	0.12	T
Sift4G	Uncertain	0.048	D
Polyphen		0.14	B
Vest4		0.13
MutPred		0.39		Loss of solvent accessibility (P = 0.0022)
MVP		0.54
MPC		1.1
ClinPred		0.075	T
GERP RS		0.73
Varity_R		0.051
gMVP		0.53
Mutation Taster		=92/8	polymorphism

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: rs121908499; hg19: chr19-920708;