chr1-65442790-A-C

Variant names:

• chr1-65442790-A-C
• rs9436746
• NM_002303.6:c.-21+17412A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.-21+17412A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 151,958 control chromosomes in the GnomAD database, including 19,929 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 0.50 (19929 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 20 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+17412A>C		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+17412A>C		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+17412A>C		intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+17412A>C		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+17412A>C		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+17412A>C		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75857 AN: 151840 Hom.: 19914 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.454

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.589

Gnomad OTH AF: 0.519

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

GnomAD4 genome AF: 0.500 AC: 75915 AN: 151958 Hom.: 19929 Cov.: 32 AF XY: 0.492 AC XY: 36512 AN XY: 74262

African (AFR) AF: 0.371 AC: 15383 AN: 41442

American (AMR) AF: 0.557 AC: 8496 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2125 AN: 3462

East Asian (EAS) AF: 0.130 AC: 672 AN: 5178

South Asian (SAS) AF: 0.554 AC: 2665 AN: 4812

European-Finnish (FIN) AF: 0.454 AC: 4784 AN: 10538

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.589 AC: 39992 AN: 67948

Other (OTH) AF: 0.520 AC: 1097 AN: 2110

Alfa AF: 0.558 Hom.: 57486

Bravo AF: 0.503

Asia WGS AF: 0.367 AC: 1280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.1
DANN	Benign	0.91
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9436746; hg19: chr1-65908473;