NM_002303.6:c.-122T>C

Variant names:

• chr1-65420715-T-C
• rs3790435
• NM_002303.6:c.-122T>C

Variant summary

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

The NM_002303.6(LEPR):​c.-122T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,580,160 control chromosomes in the GnomAD database, including 186,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18532 hom., cov: 32)
  • Exomes 𝑓: 0.48 (168324 hom.)
• Consequence: LEPR NM_002303.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0840
• Publications: 14 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]

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-65420715-T-C is Benign according to our data. Variant chr1-65420715-T-C is described in ClinVar as Benign. ClinVar VariationId is 297982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. 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
	LEPR	NM_002303.6	MANE Select	c.-122T>C		5_prime_UTR	Exon 1 of 20	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.-10T>C		5_prime_UTR	Exon 1 of 4	NP_059996.1	O15243
	LEPR	NM_001003680.3		c.-122T>C		5_prime_UTR	Exon 1 of 20	NP_001003680.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-122T>C		5_prime_UTR	Exon 1 of 20	ENSP00000330393.7	P48357-1
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.-10T>C		5_prime_UTR	Exon 1 of 4	ENSP00000360104.4	O15243
	LEPR	ENST00000371059.7	TSL:1	c.-122T>C		5_prime_UTR	Exon 1 of 20	ENSP00000360098.3	P48357-3

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74085 AN: 151938 Hom.: 18511 Cov.: 32

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.489

GnomAD2 exomes AF: 0.506 AC: 97509 AN: 192778 AF XY: 0.507

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.500

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.470

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.480 AC: 684802 AN: 1428104 Hom.: 168324 Cov.: 50 AF XY: 0.482 AC XY: 340566 AN XY: 707144

African (AFR) AF: 0.490 AC: 16078 AN: 32784

American (AMR) AF: 0.491 AC: 18595 AN: 37848

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 11806 AN: 25390

East Asian (EAS) AF: 0.856 AC: 32672 AN: 38190

South Asian (SAS) AF: 0.575 AC: 46860 AN: 81530

European-Finnish (FIN) AF: 0.474 AC: 24020 AN: 50660

Middle Eastern (MID) AF: 0.454 AC: 2436 AN: 5366

European-Non Finnish (NFE) AF: 0.459 AC: 503319 AN: 1097152

Other (OTH) AF: 0.490 AC: 29016 AN: 59184

GnomAD4 genome AF: 0.488 AC: 74154 AN: 152056 Hom.: 18532 Cov.: 32 AF XY: 0.492 AC XY: 36562 AN XY: 74322

African (AFR) AF: 0.493 AC: 20455 AN: 41478

American (AMR) AF: 0.470 AC: 7194 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1564 AN: 3466

East Asian (EAS) AF: 0.857 AC: 4422 AN: 5160

South Asian (SAS) AF: 0.589 AC: 2842 AN: 4824

European-Finnish (FIN) AF: 0.475 AC: 5015 AN: 10564

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.457 AC: 31052 AN: 67952

Other (OTH) AF: 0.491 AC: 1037 AN: 2114

Alfa AF: 0.471 Hom.: 13972

Bravo AF: 0.485

Asia WGS AF: 0.666 AC: 2314 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	not provided (1)
-	-	1	Obesity due to leptin receptor gene deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		-0.084
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs3790435; hg19: chr1-65886398;