rs10889553

Variant names:

• chr1-65440582-G-A
• rs10889553
• NM_002303.6:c.-21+15204G>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.-21+15204G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,128 control chromosomes in the GnomAD database, including 2,326 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 0.13 (2326 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+15204G>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+15204G>A		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+15204G>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.-21+15204G>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+15204G>A		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+15204G>A		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19324 AN: 152010 Hom.: 2321 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0620

Gnomad EAS AF: 0.0242

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.127 AC: 19353 AN: 152128 Hom.: 2326 Cov.: 31 AF XY: 0.126 AC XY: 9348 AN XY: 74378

African (AFR) AF: 0.319 AC: 13206 AN: 41456

American (AMR) AF: 0.0615 AC: 940 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 215 AN: 3470

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5184

South Asian (SAS) AF: 0.0946 AC: 456 AN: 4818

European-Finnish (FIN) AF: 0.0708 AC: 750 AN: 10594

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3360 AN: 67996

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.0977 Hom.: 232

Bravo AF: 0.133

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.81
PhyloP100		0.076
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: rs10889553; hg19: chr1-65906265;