rs9436747

Positions:

• chr1-65445924-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.-21+20546T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,030 control chromosomes in the GnomAD database, including 24,450 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24450 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.522

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+20546T>C		intron_variant		ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+20546T>C		intron_variant			NP_001003680.1
LEPR	NM_001003679.3	c.-21+20546T>C		intron_variant			NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+20546T>C		intron_variant		1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+20546T>C		intron_variant		1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+20546T>C		intron_variant		1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84913 AN: 151914 Hom.: 24431 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.585

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

GnomAD4 genome AF: 0.559 AC: 84972 AN: 152030 Hom.: 24450 Cov.: 32 AF XY: 0.551 AC XY: 40961 AN XY: 74314

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.595

Gnomad4 ASJ AF: 0.729

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.616

Gnomad4 OTH AF: 0.585

Alfa AF: 0.587 Hom.: 3406

Bravo AF: 0.565

Asia WGS AF: 0.394 AC: 1369 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.83

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: rs9436747; hg19: chr1-65911607;