chr19-917718-G-A

Variant names:

• chr19-917718-G-A
• rs780363542
• NM_032551.5:c.216G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4 BP6_Moderate BP7 BS1

The NM_032551.5(KISS1R):​c.216G>A​(p.Pro72Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,606,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: KISS1R NM_032551.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.57
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP6: Variant 19-917718-G-A is Benign according to our data. Variant chr19-917718-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1554387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000985 (15/152228) while in subpopulation AMR AF = 0.000981 (15/15284). AF 95% confidence interval is 0.000604. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.216G>A	p.Pro72Pro	synonymous	Exon 1 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.216G>A	p.Pro72Pro	synonymous	Exon 1 of 5	ENSP00000234371.3	Q969F8
	KISS1R	ENST00000909146.1		c.216G>A	p.Pro72Pro	synonymous	Exon 1 of 5	ENSP00000579205.1
	KISS1R	ENST00000606939.2	TSL:5	c.216G>A	p.Pro72Pro	synonymous	Exon 1 of 4	ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000203 AC: 47 AN: 231574 AF XY: 0.000189

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000323 AC: 47 AN: 1454556 Hom.: 0 Cov.: 32 AF XY: 0.0000318 AC XY: 23 AN XY: 723130

African (AFR) AF: 0.00 AC: 0 AN: 33218

American (AMR) AF: 0.000997 AC: 44 AN: 44134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109094

Other (OTH) AF: 0.0000333 AC: 2 AN: 60044

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.000981 AC: 15 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	KISS1R-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	12
DANN	Uncertain	0.98
PhyloP100		2.6
PromoterAI		0.021	Neutral

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: rs780363542; hg19: chr19-917718; COSMIC: COSV99311949; COSMIC: COSV99311949;