chr1-65428811-C-G

Variant names:

• chr1-65428811-C-G
• rs17127618
• NM_002303.6:c.-21+3433C>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.-21+3433C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 151,930 control chromosomes in the GnomAD database, including 2,050 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 0.16 (2050 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.212
• 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]

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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+3433C>G		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPROT	NM_017526.5	c.93-1051C>G		intron_variant	Intron 2 of 3	ENST00000371065.9	NP_059996.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+3433C>G		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPROT	ENST00000371065.9	c.93-1051C>G		intron_variant	Intron 2 of 3	1	NM_017526.5	ENSP00000360104.4

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24486 AN: 151812 Hom.: 2048 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.140

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

GnomAD4 genome AF: 0.161 AC: 24506 AN: 151930 Hom.: 2050 Cov.: 32 AF XY: 0.160 AC XY: 11861 AN XY: 74268

African (AFR) AF: 0.189 AC: 7844 AN: 41414

American (AMR) AF: 0.184 AC: 2806 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.116 AC: 601 AN: 5170

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4824

European-Finnish (FIN) AF: 0.0784 AC: 825 AN: 10518

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10333 AN: 67952

Other (OTH) AF: 0.140 AC: 296 AN: 2108

Alfa AF: 0.0749 Hom.: 99

Bravo AF: 0.170

Asia WGS AF: 0.173 AC: 605 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.70
PhyloP100		0.21
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: rs17127618; hg19: chr1-65894494;