rs3790437

Positions:

• chr1-65619750-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2396-178A>G		intron_variant		ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2396-178A>G		intron_variant		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

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0604

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.178

Alfa AF: 0.170 Hom.: 1280

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.5
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs3790437; hg19: chr1-66085433; COSMIC: COSV60750173; COSMIC: COSV60750173;