1-65616108-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002303.6(LEPR):c.2096C>T(p.Thr699Met) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,614,158 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (22 hom.)
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.52

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063533783).
• BP6: Variant 1-65616108-C-T is Benign according to our data. Variant chr1-65616108-C-T is described in ClinVar as [Benign]. Clinvar id is 393364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65616108-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00961 (1464/152308) while in subpopulation AFR AF= 0.0338 (1404/41566). AF 95% confidence interval is 0.0323. There are 20 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.2096C>T	p.Thr699Met	missense_variant	15/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.2096C>T	p.Thr699Met	missense_variant	15/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152190 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00251 AC: 632 AN: 251406 Hom.: 9 AF XY: 0.00197 AC XY: 268 AN XY: 135870

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000920 AC: 1345 AN: 1461850 Hom.: 22 Cov.: 32 AF XY: 0.000777 AC XY: 565 AN XY: 727222

Gnomad4 AFR exome AF: 0.0333

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00961 AC: 1464 AN: 152308 Hom.: 20 Cov.: 32 AF XY: 0.00944 AC XY: 703 AN XY: 74482

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00177 Hom.: 9

Bravo AF: 0.0114

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00320 AC: 388

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 21, 2018

ACMG criteria: BA1 (3.6% in Africans in gnomAD), BS2 (15 homozygotes in gnomAD)= benign (BP4/3 predictors + PP3/7 predictors + REVEL: 0.271: conflicting evidence, not using) -

Obesity due to leptin receptor gene deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;.
MetaRNN	Benign	0.0064	T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	2.9	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D;D;D;D;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.85
MVP		0.66
MPC		0.54
ClinPred		0.027	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.61

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: rs34499590; hg19: chr1-66081791; COSMIC: COSV60751596; COSMIC: COSV60751596;