chr1-65420676-C-T

Variant names:

• chr1-65420676-C-T
• rs372078226
• NM_002303.6:c.-161C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002303.6(LEPR):​c.-161C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,562,418 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (22 hom.)
• Consequence: LEPR NM_002303.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.11
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00441 (672/152254) while in subpopulation AMR AF = 0.00738 (113/15302). AF 95% confidence interval is 0.00628. There are 4 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.-49C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_059996.1	O15243
	LEPR	NM_002303.6	MANE Select	c.-161C>T		5_prime_UTR	Exon 1 of 20	NP_002294.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000330393.7	P48357-1
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.-49C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000360104.4	O15243
	LEPR	ENST00000371059.7	TSL:1	c.-161C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000360098.3	P48357-3

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152138 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00668

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00404 AC: 677 AN: 167734 AF XY: 0.00361

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00376

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.00687

Gnomad OTH exome AF: 0.00550

GnomAD4 exome AF: 0.00568 AC: 8014 AN: 1410164 Hom.: 22 Cov.: 30 AF XY: 0.00539 AC XY: 3757 AN XY: 696570

African (AFR) AF: 0.00105 AC: 34 AN: 32240

American (AMR) AF: 0.00441 AC: 159 AN: 36024

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 100 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 36872

South Asian (SAS) AF: 0.000362 AC: 29 AN: 80152

European-Finnish (FIN) AF: 0.00199 AC: 99 AN: 49632

Middle Eastern (MID) AF: 0.00320 AC: 15 AN: 4688

European-Non Finnish (NFE) AF: 0.00668 AC: 7265 AN: 1086982

Other (OTH) AF: 0.00536 AC: 313 AN: 58430

GnomAD4 genome AF: 0.00441 AC: 672 AN: 152254 Hom.: 4 Cov.: 31 AF XY: 0.00427 AC XY: 318 AN XY: 74442

African (AFR) AF: 0.00128 AC: 53 AN: 41552

American (AMR) AF: 0.00738 AC: 113 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00668 AC: 454 AN: 67990

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00470

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Monogenic Non-Syndromic Obesity (1)
-	1	-	Obesity due to leptin receptor gene deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.92
PhyloP100		-1.1
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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: rs372078226; hg19: chr1-65886359;