rs3790437

Variant names:

• chr1-65619750-A-G
• rs3790437
• NM_002303.6:c.2396-178A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002303.6(LEPR):​c.2396-178A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,180 control chromosomes in the GnomAD database, including 2,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (2535 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.256
• Publications: 15 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-65619750-A-G is Benign according to our data. Variant chr1-65619750-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2396-178A>G		intron_variant	Intron 16 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2396-178A>G		intron_variant	Intron 16 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26846 AN: 152062 Hom.: 2526 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.179

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.177 AC: 26884 AN: 152180 Hom.: 2535 Cov.: 32 AF XY: 0.175 AC XY: 12992 AN XY: 74410

African (AFR) AF: 0.197 AC: 8189 AN: 41512

American (AMR) AF: 0.207 AC: 3164 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3470

East Asian (EAS) AF: 0.0604 AC: 313 AN: 5186

South Asian (SAS) AF: 0.128 AC: 616 AN: 4824

European-Finnish (FIN) AF: 0.125 AC: 1326 AN: 10602

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

European-Non Finnish (NFE) AF: 0.174 AC: 11848 AN: 67992

Other (OTH) AF: 0.178 AC: 376 AN: 2112

Alfa AF: 0.175 Hom.: 1774

Bravo AF: 0.181

Asia WGS AF: 0.103 AC: 357 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.74
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3790437; hg19: chr1-66085433; COSMIC: COSV60750173; COSMIC: COSV60750173;