chr1-65570056-T-A

Position:

• chr1-65570056-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.41-417T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,170 control chromosomes in the GnomAD database, including 3,793 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 (3793 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.41-417T>A		intron_variant		ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.41-417T>A		intron_variant		1	NM_002303.6	ENSP00000330393	P4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32657 AN: 152052 Hom.: 3789 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0641

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.215

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

GnomAD4 genome AF: 0.215 AC: 32675 AN: 152170 Hom.: 3793 Cov.: 33 AF XY: 0.215 AC XY: 16014 AN XY: 74396

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0638

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.217

Alfa AF: 0.131 Hom.: 261

Bravo AF: 0.203

Asia WGS AF: 0.232 AC: 804 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.3
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs3790432; hg19: chr1-66035739;