chr1-65425307-C-T

Variant names:

• chr1-65425307-C-T
• rs13306523
• NM_002303.6:c.-92C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BA1

The NM_002303.6(LEPR):​c.-92C>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 0.00435 in 1,612,392 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0068 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (165 hom.)
• Consequence: LEPR NM_002303.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.785
• Publications: 6 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-65425307-C-T is Benign according to our data. Variant chr1-65425307-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 297984.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0501 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.-92C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.21C>T	p.Leu7Leu	synonymous	Exon 2 of 4	NP_059996.1	O15243
	LEPR	NM_002303.6	MANE Select	c.-92C>T		5_prime_UTR	Exon 2 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.-92C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-92C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	ENSP00000360098.3	P48357-3
	LEPR	ENST00000371060.7	TSL:1	c.-92C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	ENSP00000360099.3	P48357-2

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1035 AN: 152156 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00926 AC: 2289 AN: 247190 AF XY: 0.00902

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.000502

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0458

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00841

GnomAD4 exome AF: 0.00410 AC: 5985 AN: 1460118 Hom.: 165 Cov.: 30 AF XY: 0.00402 AC XY: 2921 AN XY: 726368

African (AFR) AF: 0.000960 AC: 32 AN: 33340

American (AMR) AF: 0.000543 AC: 24 AN: 44202

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26092

East Asian (EAS) AF: 0.0582 AC: 2303 AN: 39566

South Asian (SAS) AF: 0.000849 AC: 73 AN: 85940

European-Finnish (FIN) AF: 0.0513 AC: 2741 AN: 53396

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000408 AC: 454 AN: 1111488

Other (OTH) AF: 0.00577 AC: 348 AN: 60328

GnomAD4 genome AF: 0.00680 AC: 1035 AN: 152274 Hom.: 41 Cov.: 32 AF XY: 0.00942 AC XY: 701 AN XY: 74444

African (AFR) AF: 0.000914 AC: 38 AN: 41562

American (AMR) AF: 0.000850 AC: 13 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.0553 AC: 286 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0562 AC: 596 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00213 Hom.: 22

Bravo AF: 0.00255

Asia WGS AF: 0.0220 AC: 75 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	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	-0.42
CADD	Benign	6.4
DANN	Benign	0.78
PhyloP100		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=293/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13306523; hg19: chr1-65890990; COSMIC: COSV60748641;