1-65565845-T-A

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.40+240T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.968 in 148,734 control chromosomes in the GnomAD database, including 69,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.97 (69746 hom., cov: 24)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.12

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=-0.78).
• BP6: Variant 1-65565845-T-A is Benign according to our data. Variant chr1-65565845-T-A is described in ClinVar as [Benign]. Clinvar id is 1282777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.40+240T>A		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.40+240T>A		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.968 AC: 143928 AN: 148646 Hom.: 69713 Cov.: 24

Gnomad AFR AF: 0.927

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.983

Gnomad ASJ AF: 0.976

Gnomad EAS AF: 0.993

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.971

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.975

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

GnomAD4 genome AF: 0.968 AC: 144006 AN: 148734 Hom.: 69746 Cov.: 24 AF XY: 0.969 AC XY: 70198 AN XY: 72440

Gnomad4 AFR AF: 0.927

Gnomad4 AMR AF: 0.983

Gnomad4 ASJ AF: 0.976

Gnomad4 EAS AF: 0.993

Gnomad4 SAS AF: 0.992

Gnomad4 FIN AF: 0.990

Gnomad4 NFE AF: 0.982

Gnomad4 OTH AF: 0.976

Alfa AF: 0.977 Hom.: 8466

Bravo AF: 0.968

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

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.056
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs10157915; hg19: chr1-66031528; COSMIC: COSV60753541;