chr19-920542-C-G

Variant names:

• chr19-920542-C-G
• rs104894701
• NM_032551.5:c.991C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_032551.5(KISS1R):​c.991C>G​(p.Arg331Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,437,688 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R331P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.123
• Publications: 14 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1R	NM_032551.5	MANE Select	c.991C>G	p.Arg331Gly	missense	Exon 5 of 5	NP_115940.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KISS1R	ENST00000234371.10	TSL:1 MANE Select	c.991C>G	p.Arg331Gly	missense	Exon 5 of 5	ENSP00000234371.3
	KISS1R	ENST00000606939.2	TSL:5	c.*77C>G		3_prime_UTR	Exon 4 of 4	ENSP00000475639.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000216 AC: 31 AN: 1437688 Hom.: 0 Cov.: 37 AF XY: 0.0000168 AC XY: 12 AN XY: 715474

African (AFR) AF: 0.00 AC: 0 AN: 30300

American (AMR) AF: 0.00 AC: 0 AN: 42672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 36898

South Asian (SAS) AF: 0.00 AC: 0 AN: 83390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.0000272 AC: 30 AN: 1103642

Other (OTH) AF: 0.0000168 AC: 1 AN: 59466

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.12
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.83		Loss of MoRF binding (P = 0.0082)
MVP		0.79
MPC		2.1
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.94
gMVP		0.80
Mutation Taster		=23/77	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: rs104894701; hg19: chr19-920542;