rs1805134

chr1-65601426-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002303.6(LEPR):c.1029T>C(p.Ser343=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,612,898 control chromosomes in the GnomAD database, including 38,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4919 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33984 hom.)
• Consequence: LEPR NM_002303.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.467

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-65601426-T-C is Benign according to our data. Variant chr1-65601426-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 297991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65601426-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.467 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.1029T>C	p.Ser343=	synonymous_variant	9/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.1029T>C	p.Ser343=	synonymous_variant	9/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36024 AN: 151820 Hom.: 4909 Cov.: 32

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.0670

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.217 AC: 54505 AN: 250920 Hom.: 6790 AF XY: 0.224 AC XY: 30390 AN XY: 135658

Gnomad AFR exome AF: 0.339

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.0596

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.208 AC: 304579 AN: 1460960 Hom.: 33984 Cov.: 34 AF XY: 0.213 AC XY: 154954 AN XY: 726782

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.0855

Gnomad4 SAS exome AF: 0.338

Gnomad4 FIN exome AF: 0.227

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.220

GnomAD4 genome AF: 0.237 AC: 36077 AN: 151938 Hom.: 4919 Cov.: 32 AF XY: 0.237 AC XY: 17597 AN XY: 74264

Gnomad4 AFR AF: 0.329

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.317

Gnomad4 EAS AF: 0.0670

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.226

Alfa AF: 0.219 Hom.: 2213

Bravo AF: 0.232

Asia WGS AF: 0.275 AC: 955 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.207

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	This variant is associated with the following publications: (PMID: 9175732, 11380591, 12646666) -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Monogenic Non-Syndromic Obesity Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to leptin receptor gene deficiency Benign:1

Likely 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	-0.79
Cadd	Benign	5.8
Dann	Benign	0.63

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: rs1805134; hg19: chr1-66067109; COSMIC: COSV60765898;