rs1805094

Variant names:

• chr1-65610269-G-C
• rs1805094
• NM_002303.6:c.1968G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-65610269-G-C
• chr1-65610269-G-T

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.1968G>C​(p.Lys656Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,611,922 control chromosomes in the GnomAD database, including 23,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2494 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21117 hom.)
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.469
• Publications: 220 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019337535).
• BP6: Variant 1-65610269-G-C is Benign according to our data. Variant chr1-65610269-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.197 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.1968G>C	p.Lys656Asn	missense	Exon 14 of 20	NP_002294.2
	LEPR	NM_001003680.3		c.1968G>C	p.Lys656Asn	missense	Exon 14 of 20	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.1968G>C	p.Lys656Asn	missense	Exon 13 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.1968G>C	p.Lys656Asn	missense	Exon 14 of 20	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.1968G>C	p.Lys656Asn	missense	Exon 14 of 20	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.1968G>C	p.Lys656Asn	missense	Exon 13 of 19	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26619 AN: 151938 Hom.: 2495 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0563

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.159 AC: 39679 AN: 250258 AF XY: 0.160

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0522

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.167 AC: 243993 AN: 1459864 Hom.: 21117 Cov.: 33 AF XY: 0.167 AC XY: 121425 AN XY: 726234

African (AFR) AF: 0.194 AC: 6482 AN: 33418

American (AMR) AF: 0.170 AC: 7566 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5636 AN: 26102

East Asian (EAS) AF: 0.0779 AC: 3088 AN: 39664

South Asian (SAS) AF: 0.143 AC: 12277 AN: 85984

European-Finnish (FIN) AF: 0.123 AC: 6555 AN: 53394

Middle Eastern (MID) AF: 0.246 AC: 1413 AN: 5740

European-Non Finnish (NFE) AF: 0.172 AC: 190856 AN: 1110622

Other (OTH) AF: 0.168 AC: 10120 AN: 60310

GnomAD4 genome AF: 0.175 AC: 26632 AN: 152058 Hom.: 2494 Cov.: 33 AF XY: 0.173 AC XY: 12848 AN XY: 74330

African (AFR) AF: 0.194 AC: 8060 AN: 41480

American (AMR) AF: 0.203 AC: 3101 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3466

East Asian (EAS) AF: 0.0566 AC: 293 AN: 5180

South Asian (SAS) AF: 0.127 AC: 609 AN: 4812

European-Finnish (FIN) AF: 0.126 AC: 1331 AN: 10568

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11814 AN: 67980

Other (OTH) AF: 0.176 AC: 371 AN: 2106

Alfa AF: 0.146 Hom.: 633

Bravo AF: 0.179

TwinsUK AF: 0.180 AC: 668

ALSPAC AF: 0.164 AC: 633

ESP6500AA AF: 0.188 AC: 828

ESP6500EA AF: 0.171 AC: 1467

ExAC AF: 0.158 AC: 19136

Asia WGS AF: 0.0970 AC: 336 AN: 3478

EpiCase AF: 0.193

EpiControl AF: 0.194

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.41
DANN	Benign	0.92
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.47
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	0.45	T
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.030
MutPred		0.16		Loss of methylation at K656 (P = 0.0183)
MPC		0.14
ClinPred		0.0037	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.44
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1805094; hg19: chr1-66075952; COSMIC: COSV60750073; COSMIC: COSV60750073;