chr1-65505472-C-G

Variant names:

• chr1-65505472-C-G
• rs12079231
• NM_002303.6:c.-20-60074C>G

Variant summary

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

The NM_002303.6(LEPR):​c.-20-60074C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,096 control chromosomes in the GnomAD database, including 3,589 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 0.21 (3589 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-20-60074C>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-20-60074C>G		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001003679.3		c.-20-60074C>G		intron	N/A	NP_001003679.1	P48357-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-20-60074C>G		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-20-60074C>G		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000371060.7	TSL:1	c.-20-60074C>G		intron	N/A	ENSP00000360099.3	P48357-2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31202 AN: 151978 Hom.: 3585 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.205 AC: 31224 AN: 152096 Hom.: 3589 Cov.: 32 AF XY: 0.204 AC XY: 15148 AN XY: 74358

African (AFR) AF: 0.279 AC: 11568 AN: 41476

American (AMR) AF: 0.236 AC: 3597 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3470

East Asian (EAS) AF: 0.0452 AC: 234 AN: 5178

South Asian (SAS) AF: 0.285 AC: 1374 AN: 4814

European-Finnish (FIN) AF: 0.0784 AC: 831 AN: 10606

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11872 AN: 67976

Other (OTH) AF: 0.211 AC: 445 AN: 2112

Alfa AF: 0.194 Hom.: 397

Bravo AF: 0.220

Asia WGS AF: 0.176 AC: 618 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.8
DANN	Benign	0.57
PhyloP100		0.31
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: rs12079231; hg19: chr1-65971155;