rs350132

Variant names:

• chr19-920642-T-A
• rs350132
• NM_032551.5:c.1091T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-920642-T-A
• chr19-920642-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032551.5(KISS1R):​c.1091T>A​(p.Leu364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,356,162 control chromosomes in the GnomAD database, including 396,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48506 hom., cov: 33)
  • Exomes 𝑓: 0.76 (347977 hom.)
• Consequence: KISS1R NM_032551.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: -0.237
• Publications: 30 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.9137126E-7).
• BP6: Variant 19-920642-T-A is Benign according to our data. Variant chr19-920642-T-A is described in ClinVar as Benign. ClinVar VariationId is 447660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

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.1091T>A	p.Leu364His	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.1091T>A	p.Leu364His	missense	Exon 5 of 5	ENSP00000234371.3	Q969F8
	KISS1R	ENST00000909146.1		c.1085T>A	p.Leu362His	missense	Exon 5 of 5	ENSP00000579205.1
	KISS1R	ENST00000606939.2	TSL:5	c.*177T>A		3_prime_UTR	Exon 4 of 4	ENSP00000475639.1	U3KQ86

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120783 AN: 151762 Hom.: 48459 Cov.: 33

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.827

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.800

GnomAD2 exomes AF: 0.781 AC: 9423 AN: 12060 AF XY: 0.777

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.842

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.788

GnomAD4 exome AF: 0.760 AC: 914936 AN: 1204292 Hom.: 347977 Cov.: 57 AF XY: 0.760 AC XY: 445591 AN XY: 586324

African (AFR) AF: 0.904 AC: 21661 AN: 23962

American (AMR) AF: 0.737 AC: 7721 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 13820 AN: 16520

East Asian (EAS) AF: 0.759 AC: 21168 AN: 27886

South Asian (SAS) AF: 0.752 AC: 34589 AN: 45994

European-Finnish (FIN) AF: 0.774 AC: 22671 AN: 29278

Middle Eastern (MID) AF: 0.788 AC: 3311 AN: 4202

European-Non Finnish (NFE) AF: 0.754 AC: 751419 AN: 996262

Other (OTH) AF: 0.776 AC: 38576 AN: 49706

GnomAD4 genome AF: 0.796 AC: 120887 AN: 151870 Hom.: 48506 Cov.: 33 AF XY: 0.795 AC XY: 59010 AN XY: 74256

African (AFR) AF: 0.897 AC: 37217 AN: 41492

American (AMR) AF: 0.720 AC: 10988 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2849 AN: 3470

East Asian (EAS) AF: 0.747 AC: 3840 AN: 5144

South Asian (SAS) AF: 0.743 AC: 3588 AN: 4830

European-Finnish (FIN) AF: 0.776 AC: 8144 AN: 10500

Middle Eastern (MID) AF: 0.828 AC: 240 AN: 290

European-Non Finnish (NFE) AF: 0.760 AC: 51614 AN: 67876

Other (OTH) AF: 0.802 AC: 1686 AN: 2102

Alfa AF: 0.782 Hom.: 5459

Bravo AF: 0.796

TwinsUK AF: 0.754 AC: 2794

ALSPAC AF: 0.741 AC: 2856

ExAC AF: 0.619 AC: 28075

Asia WGS AF: 0.763 AC: 2655 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
1	-	-	Central precocious puberty 1 (1)
-	-	1	Hypogonadotropic hypogonadism 8 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.1
DANN	Benign	0.82
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-0.24
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	4.9	N
REVEL	Benign	0.090
Sift	Benign	1.0	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.039
MPC		1.1
ClinPred		0.00037	T
GERP RS		-0.61
Varity_R		0.069
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs350132; hg19: chr19-920642; COSMIC: COSV52257058; COSMIC: COSV52257058;