rs17415296

Variant names:

• chr1-65633330-C-A
• rs17415296
• ENST00000371060.7:c.*161C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65633330-C-A
• chr1-65633330-C-T

Variant summary

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

The ENST00000371060.7(LEPR):​c.*161C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,379,294 control chromosomes in the GnomAD database, including 19,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1739 hom., cov: 32)
  • Exomes 𝑓: 0.16 (17264 hom.)
• Consequence: LEPR ENST00000371060.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.260
• Publications: 24 publications found

Genes affected

LEPR (HGNC:6554): (leptin receptor) The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-65633330-C-A is Benign according to our data. Variant chr1-65633330-C-A is described in ClinVar as Benign. ClinVar VariationId is 1259804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371060.7. 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
	LEPR	NM_002303.6	MANE Select	c.2674-2861C>A		intron	N/A	NP_002294.2
	LEPR	NM_001003679.3		c.*161C>A		3_prime_UTR	Exon 20 of 20	NP_001003679.1
	LEPR	NM_001198689.2		c.*161C>A		3_prime_UTR	Exon 19 of 19	NP_001185618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000371060.7	TSL:1	c.*161C>A		3_prime_UTR	Exon 20 of 20	ENSP00000360099.3
	LEPR	ENST00000616738.4	TSL:1	c.*161C>A		3_prime_UTR	Exon 19 of 19	ENSP00000483390.1
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.2674-2861C>A		intron	N/A	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20774 AN: 151896 Hom.: 1736 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.0598

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.165 AC: 202173 AN: 1227280 Hom.: 17264 Cov.: 25 AF XY: 0.165 AC XY: 98308 AN XY: 595664

African (AFR) AF: 0.0559 AC: 1505 AN: 26906

American (AMR) AF: 0.174 AC: 3234 AN: 18588

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 4240 AN: 19582

East Asian (EAS) AF: 0.0831 AC: 2742 AN: 32992

South Asian (SAS) AF: 0.141 AC: 6652 AN: 47230

European-Finnish (FIN) AF: 0.121 AC: 3485 AN: 28908

Middle Eastern (MID) AF: 0.240 AC: 1143 AN: 4760

European-Non Finnish (NFE) AF: 0.171 AC: 171069 AN: 997720

Other (OTH) AF: 0.160 AC: 8103 AN: 50594

GnomAD4 genome AF: 0.137 AC: 20788 AN: 152014 Hom.: 1739 Cov.: 32 AF XY: 0.136 AC XY: 10088 AN XY: 74278

African (AFR) AF: 0.0580 AC: 2405 AN: 41494

American (AMR) AF: 0.190 AC: 2899 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 760 AN: 3470

East Asian (EAS) AF: 0.0601 AC: 311 AN: 5172

South Asian (SAS) AF: 0.128 AC: 615 AN: 4808

European-Finnish (FIN) AF: 0.126 AC: 1331 AN: 10554

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11864 AN: 67934

Other (OTH) AF: 0.150 AC: 317 AN: 2114

Alfa AF: 0.168 Hom.: 2785

Bravo AF: 0.136

Asia WGS AF: 0.0900 AC: 312 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs17415296; hg19: chr1-66099013; COSMIC: COSV62746470; COSMIC: COSV62746470;