19-919949-C-T

Position:

• chr19-919949-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032551.5(KISS1R):​c.581C>T​(p.Ala194Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.112

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KISS1R	NM_032551.5	c.581C>T	p.Ala194Val	missense_variant	4/5	ENST00000234371.10	NP_115940.2
KISS1R	XM_047439545.1	c.581C>T	p.Ala194Val	missense_variant	4/4		XP_047295501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KISS1R	ENST00000234371.10	c.581C>T	p.Ala194Val	missense_variant	4/5	1	NM_032551.5	ENSP00000234371.3
KISS1R	ENST00000606939.2	c.505+324C>T		intron_variant		5		ENSP00000475639.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000578 AC: 1 AN: 173152 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 95734

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1417932 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 702654

Gnomad4 AFR exome AF: 0.0000311

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: 9.15e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.097	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.056
Sift	Benign	0.35	T
Sift4G	Benign	0.35	T
Polyphen		0.0090	B
Vest4		0.077
MutPred		0.55		Gain of loop (P = 0.0435);
MVP		0.45
MPC		0.98
ClinPred		0.048	T
GERP RS		-0.37
Varity_R		0.11
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397514699; hg19: chr19-919949;