rs13306519

Variant names:

• chr1-65572246-C-G
• rs13306519
• NM_002303.6:c.371-80C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-65572246-C-G
• chr1-65572246-C-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002303.6(LEPR):​c.371-80C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,397,890 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (98 hom., cov: 29)
  • Exomes 𝑓: 0.012 (619 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.31
• Publications: 7 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-65572246-C-G is Benign according to our data. Variant chr1-65572246-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1222942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 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.371-80C>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.371-80C>G		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.371-80C>G		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.371-80C>G		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.371-80C>G		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.371-80C>G		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 1996 AN: 131628 Hom.: 97 Cov.: 29

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00501

Gnomad ASJ AF: 0.000615

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.00855

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.0166

GnomAD4 exome AF: 0.0118 AC: 14954 AN: 1266224 Hom.: 619 AF XY: 0.0114 AC XY: 7119 AN XY: 623906

African (AFR) AF: 0.00111 AC: 29 AN: 26120

American (AMR) AF: 0.00242 AC: 46 AN: 19018

Ashkenazi Jewish (ASJ) AF: 0.000473 AC: 10 AN: 21150

East Asian (EAS) AF: 0.175 AC: 5620 AN: 32182

South Asian (SAS) AF: 0.00389 AC: 242 AN: 62188

European-Finnish (FIN) AF: 0.0299 AC: 1121 AN: 37502

Middle Eastern (MID) AF: 0.00304 AC: 11 AN: 3624

European-Non Finnish (NFE) AF: 0.00677 AC: 6851 AN: 1012204

Other (OTH) AF: 0.0196 AC: 1024 AN: 52236

GnomAD4 genome AF: 0.0151 AC: 1994 AN: 131666 Hom.: 98 Cov.: 29 AF XY: 0.0176 AC XY: 1113 AN XY: 63214

African (AFR) AF: 0.00346 AC: 118 AN: 34128

American (AMR) AF: 0.00501 AC: 67 AN: 13376

Ashkenazi Jewish (ASJ) AF: 0.000615 AC: 2 AN: 3254

East Asian (EAS) AF: 0.205 AC: 952 AN: 4644

South Asian (SAS) AF: 0.00833 AC: 34 AN: 4082

European-Finnish (FIN) AF: 0.0490 AC: 336 AN: 6858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00728 AC: 455 AN: 62518

Other (OTH) AF: 0.0166 AC: 30 AN: 1812

Alfa AF: 0.00953 Hom.: 5

Bravo AF: 0.0119

Asia WGS AF: 0.0870 AC: 298 AN: 3442

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.67
PhyloP100		2.3
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: rs13306519; hg19: chr1-66037929;