1-65420715-T-C

Position:

• chr1-65420715-T-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-122T>C		5_prime_UTR_variant	1/20	ENST00000349533.11
LEPROT	NM_017526.5	c.-10T>C		5_prime_UTR_variant	1/4	ENST00000371065.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-122T>C		5_prime_UTR_variant	1/20	1	NM_002303.6	P4
LEPROT	ENST00000371065.9	c.-10T>C		5_prime_UTR_variant	1/4	1	NM_017526.5	P1

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

GnomAD3 exomes AF: 0.506 AC: 97509 AN: 192778 Hom.: 25845 AF XY: 0.507 AC XY: 52522 AN XY: 103664

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 SAS exome AF: 0.567

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

Gnomad4 AFR exome AF: 0.490

Gnomad4 AMR exome AF: 0.491

Gnomad4 ASJ exome AF: 0.465

Gnomad4 EAS exome AF: 0.856

Gnomad4 SAS exome AF: 0.575

Gnomad4 FIN exome AF: 0.474

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.490

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

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.470

Gnomad4 ASJ AF: 0.451

Gnomad4 EAS AF: 0.857

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.491

Alfa AF: 0.464 Hom.: 7176

Bravo AF: 0.485

Asia WGS AF: 0.666 AC: 2314 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic Non-Syndromic Obesity Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Obesity due to leptin receptor gene deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs3790435; hg19: chr1-65886398;