chr1-65503869-G-A

Variant names:

• chr1-65503869-G-A
• rs10889556
• NM_002303.6:c.-20-61677G>A

Variant summary

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

The NM_002303.6(LEPR):​c.-20-61677G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 151,588 control chromosomes in the GnomAD database, including 34,873 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 0.67 (34873 hom., cov: 30)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.428
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-61677G>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-20-61677G>A		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-20-61677G>A		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.-20-61677G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-20-61677G>A		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-20-61677G>A		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101271 AN: 151470 Hom.: 34855 Cov.: 30

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.807

Gnomad AMR AF: 0.686

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.709

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

GnomAD4 genome AF: 0.669 AC: 101339 AN: 151588 Hom.: 34873 Cov.: 30 AF XY: 0.663 AC XY: 49071 AN XY: 74030

African (AFR) AF: 0.621 AC: 25652 AN: 41276

American (AMR) AF: 0.686 AC: 10426 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2826 AN: 3470

East Asian (EAS) AF: 0.134 AC: 686 AN: 5138

South Asian (SAS) AF: 0.729 AC: 3488 AN: 4784

European-Finnish (FIN) AF: 0.610 AC: 6373 AN: 10456

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49414 AN: 67948

Other (OTH) AF: 0.706 AC: 1486 AN: 2106

Alfa AF: 0.706 Hom.: 23498

Bravo AF: 0.670

Asia WGS AF: 0.499 AC: 1738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.88
DANN	Benign	0.44
PhyloP100		-0.43
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: rs10889556; hg19: chr1-65969552;