1-65597434-G-T

Variant names:

• chr1-65597434-G-T
• rs12405556
• NM_002303.6:c.849+841G>T

Variant summary

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

The NM_002303.6(LEPR):​c.849+841G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 151,936 control chromosomes in the GnomAD database, including 6,341 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 0.26 (6341 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 23 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.849+841G>T		intron_variant	Intron 7 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.849+841G>T		intron_variant	Intron 7 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39223 AN: 151818 Hom.: 6338 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.248

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

GnomAD4 genome AF: 0.258 AC: 39235 AN: 151936 Hom.: 6341 Cov.: 32 AF XY: 0.264 AC XY: 19609 AN XY: 74246

African (AFR) AF: 0.157 AC: 6527 AN: 41478

American (AMR) AF: 0.284 AC: 4333 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 491 AN: 3468

East Asian (EAS) AF: 0.818 AC: 4221 AN: 5158

South Asian (SAS) AF: 0.173 AC: 835 AN: 4820

European-Finnish (FIN) AF: 0.384 AC: 4047 AN: 10530

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18070 AN: 67920

Other (OTH) AF: 0.252 AC: 529 AN: 2100

Alfa AF: 0.240 Hom.: 5965

Bravo AF: 0.250

Asia WGS AF: 0.414 AC: 1436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.67
PhyloP100		-0.054
Mutation Taster		=100/0	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: rs12405556; hg19: chr1-66063117;