rs4655555

Variant names:

• chr1-65614586-T-A
• rs4655555
• NM_002303.6:c.1996-1422T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65614586-T-A
• chr1-65614586-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.1996-1422T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,072 control chromosomes in the GnomAD database, including 4,517 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 0.21 (4517 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01
• Publications: 8 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.1996-1422T>A		intron_variant	Intron 14 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.1996-1422T>A		intron_variant	Intron 14 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31855 AN: 151954 Hom.: 4514 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.0855

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 31876 AN: 152072 Hom.: 4517 Cov.: 32 AF XY: 0.218 AC XY: 16190 AN XY: 74330

African (AFR) AF: 0.153 AC: 6360 AN: 41514

American (AMR) AF: 0.242 AC: 3693 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 297 AN: 3472

East Asian (EAS) AF: 0.775 AC: 3998 AN: 5158

South Asian (SAS) AF: 0.128 AC: 619 AN: 4818

European-Finnish (FIN) AF: 0.347 AC: 3658 AN: 10550

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12740 AN: 67968

Other (OTH) AF: 0.205 AC: 432 AN: 2108

Alfa AF: 0.202 Hom.: 432

Bravo AF: 0.205

Asia WGS AF: 0.381 AC: 1324 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.83
PhyloP100		-2.0
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: rs4655555; hg19: chr1-66080269; COSMIC: COSV60755495; COSMIC: COSV60755495;