rs6672331

Positions:

• chr1-65510164-G-C
• chr1-65510164-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002303.6(LEPR):​c.-20-55382G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 152,208 control chromosomes in the GnomAD database, including 36 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 0.020 (36 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210

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=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0202 (3071/152208) while in subpopulation NFE AF= 0.0308 (2095/67996). AF 95% confidence interval is 0.0297. There are 36 homozygotes in gnomad4. There are 1486 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-55382G>C		intron_variant		ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-20-55382G>C		intron_variant			NP_001003680.1
LEPR	NM_001003679.3	c.-20-55382G>C		intron_variant			NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-20-55382G>C		intron_variant		1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-20-55382G>C		intron_variant		1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-20-55382G>C		intron_variant		1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3071 AN: 152090 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0308

Gnomad OTH AF: 0.0206

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

GnomAD4 genome AF: 0.0202 AC: 3071 AN: 152208 Hom.: 36 Cov.: 32 AF XY: 0.0200 AC XY: 1486 AN XY: 74432

Gnomad4 AFR AF: 0.00523

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00788

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0308

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0290 Hom.: 9

Bravo AF: 0.0181

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.55

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: rs6672331; hg19: chr1-65975847;