rs1805134

Variant names:

• chr1-65601426-T-C
• rs1805134
• NM_002303.6:c.1029T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002303.6(LEPR):​c.1029T>C​(p.Ser343Ser) 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:8
• Conservation: PhyloP100: 0.467
• Publications: 50 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 297991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1029T>C	p.Ser343Ser	synonymous	Exon 9 of 20	NP_002294.2
	LEPR	NM_001003680.3		c.1029T>C	p.Ser343Ser	synonymous	Exon 9 of 20	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.1029T>C	p.Ser343Ser	synonymous	Exon 8 of 19	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.1029T>C	p.Ser343Ser	synonymous	Exon 9 of 20	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.1029T>C	p.Ser343Ser	synonymous	Exon 9 of 20	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.1029T>C	p.Ser343Ser	synonymous	Exon 8 of 19	ENSP00000340884.8	P48357-4

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

GnomAD2 exomes AF: 0.217 AC: 54505 AN: 250920 AF XY: 0.224

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 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

African (AFR) AF: 0.333 AC: 11145 AN: 33458

American (AMR) AF: 0.133 AC: 5947 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7827 AN: 26122

East Asian (EAS) AF: 0.0855 AC: 3389 AN: 39650

South Asian (SAS) AF: 0.338 AC: 29138 AN: 86220

European-Finnish (FIN) AF: 0.227 AC: 12081 AN: 53238

Middle Eastern (MID) AF: 0.205 AC: 1168 AN: 5708

European-Non Finnish (NFE) AF: 0.198 AC: 220608 AN: 1111494

Other (OTH) AF: 0.220 AC: 13276 AN: 60362

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

African (AFR) AF: 0.329 AC: 13649 AN: 41462

American (AMR) AF: 0.170 AC: 2598 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1097 AN: 3464

East Asian (EAS) AF: 0.0670 AC: 347 AN: 5182

South Asian (SAS) AF: 0.342 AC: 1648 AN: 4822

European-Finnish (FIN) AF: 0.215 AC: 2276 AN: 10584

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13812 AN: 67862

Other (OTH) AF: 0.226 AC: 477 AN: 2110

Alfa AF: 0.217 Hom.: 6902

Bravo AF: 0.232

Asia WGS AF: 0.275 AC: 955 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.207

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	Obesity due to leptin receptor gene deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.63
PhyloP100		0.47
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: rs1805134; hg19: chr1-66067109; COSMIC: COSV60765898;