NM_002303.6:c.370+16G>T

Variant names:

• chr1-65570818-G-T
• rs2186248
• NM_002303.6:c.370+16G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002303.6(LEPR):​c.370+16G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 1 in 152,364 control chromosomes in the GnomAD database, including 76,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (76133 hom., cov: 34)
  • Exomes 𝑓: 1.0 (686481 hom.)
  • Failed GnomAD Quality Control
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.452
• 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]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-65570818-G-T is Benign according to our data. Variant chr1-65570818-G-T is described in ClinVar as Benign. ClinVar VariationId is 487357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.994 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.370+16G>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.370+16G>T		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.370+16G>T		intron	N/A	NP_001185616.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.370+16G>T		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.370+16G>T		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.370+16G>T		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 1.00 AC: 152198 AN: 152246 Hom.: 76075 Cov.: 34

Gnomad AFR AF: 0.999

Gnomad AMI AF: 1.00

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 1.00

GnomAD2 exomes AF: 1.00 AC: 187711 AN: 187736 AF XY: 1.00

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 1.00 AC: 1373030 AN: 1373100 Hom.: 686481 Cov.: 29 AF XY: 1.00 AC XY: 674306 AN XY: 674334

African (AFR) AF: 0.998 AC: 30431 AN: 30488

American (AMR) AF: 1.00 AC: 30552 AN: 30554

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 20908 AN: 20908

East Asian (EAS) AF: 1.00 AC: 38888 AN: 38888

South Asian (SAS) AF: 1.00 AC: 69355 AN: 69356

European-Finnish (FIN) AF: 1.00 AC: 49665 AN: 49666

Middle Eastern (MID) AF: 1.00 AC: 4922 AN: 4922

European-Non Finnish (NFE) AF: 1.00 AC: 1071736 AN: 1071736

Other (OTH) AF: 1.00 AC: 56573 AN: 56582

GnomAD4 genome AF: 1.00 AC: 152315 AN: 152364 Hom.: 76133 Cov.: 34 AF XY: 1.00 AC XY: 74479 AN XY: 74506

African (AFR) AF: 0.999 AC: 41541 AN: 41590

American (AMR) AF: 1.00 AC: 15304 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5192 AN: 5192

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68040 AN: 68040

Other (OTH) AF: 1.00 AC: 2114 AN: 2114

Alfa AF: 1.00 Hom.: 10068

Bravo AF: 1.00

Asia WGS AF: 1.00 AC: 3474 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Obesity due to leptin receptor gene deficiency (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.31
PhyloP100		-0.45
Mutation Taster		=20/80	disease causing

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: rs2186248; hg19: chr1-66036501;