1-65623018-C-T

Variant names:

• chr1-65623018-C-T
• rs12067936
• NM_002303.6:c.2673+37C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_002303.6(LEPR):​c.2673+37C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000251 in 1,593,912 control chromosomes in the GnomAD database, including 2 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 0.000040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (1 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 12 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000236 (34/1442066) while in subpopulation EAS AF = 0.000506 (20/39524). AF 95% confidence interval is 0.000335. There are 1 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

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.2673+37C>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.2673+37C>T		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.2673+37C>T		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.2673+37C>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.2673+37C>T		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.2673+37C>T		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151846 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000208 AC: 5 AN: 240932 AF XY: 0.0000230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000372

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000236 AC: 34 AN: 1442066 Hom.: 1 Cov.: 27 AF XY: 0.0000181 AC XY: 13 AN XY: 717954

African (AFR) AF: 0.00 AC: 0 AN: 33150

American (AMR) AF: 0.00 AC: 0 AN: 44112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25922

East Asian (EAS) AF: 0.000506 AC: 20 AN: 39524

South Asian (SAS) AF: 0.00 AC: 0 AN: 85356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1095854

Other (OTH) AF: 0.0000168 AC: 1 AN: 59650

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151846 Hom.: 1 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74110

African (AFR) AF: 0.0000726 AC: 3 AN: 41310

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67962

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000143 Hom.: 6537

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.7
DANN	Benign	0.93
PhyloP100		0.066
Mutation Taster		=100/0	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: rs12067936; hg19: chr1-66088701;