1-65430244-T-C

Variant names:

• chr1-65430244-T-C
• rs9436301
• NM_002303.6:c.-21+4866T>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+4866T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 413,756 control chromosomes in the GnomAD database, including 14,292 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 0.28 (6539 hom., cov: 32)
  • Exomes 𝑓: 0.23 (7753 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0960
• Publications: 13 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]

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-21+4866T>C		intron	N/A	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.279+196T>C		intron	N/A	NP_059996.1
	LEPR	NM_001003680.3		c.-21+4866T>C		intron	N/A	NP_001003680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+4866T>C		intron	N/A	ENSP00000330393.7
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.279+196T>C		intron	N/A	ENSP00000360104.4
	LEPR	ENST00000371059.7	TSL:1	c.-21+4866T>C		intron	N/A	ENSP00000360098.3

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43099 AN: 151988 Hom.: 6530 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.233 AC: 61001 AN: 261650 Hom.: 7753 Cov.: 4 AF XY: 0.236 AC XY: 31827 AN XY: 134732

African (AFR) AF: 0.387 AC: 2920 AN: 7544

American (AMR) AF: 0.261 AC: 2089 AN: 8004

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 2371 AN: 9342

East Asian (EAS) AF: 0.0739 AC: 1705 AN: 23080

South Asian (SAS) AF: 0.309 AC: 1786 AN: 5786

European-Finnish (FIN) AF: 0.167 AC: 3773 AN: 22546

Middle Eastern (MID) AF: 0.370 AC: 906 AN: 2450

European-Non Finnish (NFE) AF: 0.248 AC: 41247 AN: 166182

Other (OTH) AF: 0.251 AC: 4204 AN: 16716

GnomAD4 genome AF: 0.284 AC: 43134 AN: 152106 Hom.: 6539 Cov.: 32 AF XY: 0.279 AC XY: 20784 AN XY: 74366

African (AFR) AF: 0.393 AC: 16306 AN: 41454

American (AMR) AF: 0.275 AC: 4196 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 902 AN: 3468

East Asian (EAS) AF: 0.118 AC: 611 AN: 5182

South Asian (SAS) AF: 0.318 AC: 1531 AN: 4808

European-Finnish (FIN) AF: 0.155 AC: 1644 AN: 10596

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16991 AN: 67996

Other (OTH) AF: 0.254 AC: 535 AN: 2110

Alfa AF: 0.260 Hom.: 18953

Bravo AF: 0.295

Asia WGS AF: 0.224 AC: 783 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.4
DANN	Benign	0.86
PhyloP100		0.096
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: rs9436301; hg19: chr1-65895927;