1-65522810-C-T

Position:

• chr1-65522810-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002303.6(LEPR):​c.-20-42736C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 150,054 control chromosomes in the GnomAD database, including 13,133 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 0.38 (13133 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.857

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-20-42736C>T		intron_variant		ENST00000349533.11
LEPR	NM_001003679.3	c.-20-42736C>T		intron_variant
LEPR	NM_001003680.3	c.-20-42736C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-20-42736C>T		intron_variant		1	NM_002303.6	P4
LEPR	ENST00000371059.7	c.-20-42736C>T		intron_variant		1
LEPR	ENST00000371060.7	c.-20-42736C>T		intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 56909 AN: 149964 Hom.: 13100 Cov.: 31

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.380 AC: 56991 AN: 150054 Hom.: 13133 Cov.: 31 AF XY: 0.380 AC XY: 27767 AN XY: 73118

Gnomad4 AFR AF: 0.636

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.370

Alfa AF: 0.309 Hom.: 4777

Bravo AF: 0.392

Asia WGS AF: 0.396 AC: 1379 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.64

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: rs1171279; hg19: chr1-65988493;