1-65538171-T-G

Variant names:

• chr1-65538171-T-G
• rs1171267
• NM_002303.6:c.-20-27375T>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.-20-27375T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 151,428 control chromosomes in the GnomAD database, including 30,202 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 0.62 (30202 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.606
• Publications: 5 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-20-27375T>G		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-20-27375T>G		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94221 AN: 151312 Hom.: 30192 Cov.: 32

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.748

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.758

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.647

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

GnomAD4 genome AF: 0.623 AC: 94273 AN: 151428 Hom.: 30202 Cov.: 32 AF XY: 0.614 AC XY: 45453 AN XY: 74030

African (AFR) AF: 0.674 AC: 27813 AN: 41284

American (AMR) AF: 0.657 AC: 10008 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2395 AN: 3464

East Asian (EAS) AF: 0.109 AC: 564 AN: 5164

South Asian (SAS) AF: 0.532 AC: 2559 AN: 4808

European-Finnish (FIN) AF: 0.509 AC: 5280 AN: 10370

Middle Eastern (MID) AF: 0.750 AC: 219 AN: 292

European-Non Finnish (NFE) AF: 0.640 AC: 43412 AN: 67816

Other (OTH) AF: 0.640 AC: 1341 AN: 2096

Alfa AF: 0.646 Hom.: 7082

Bravo AF: 0.637

Asia WGS AF: 0.351 AC: 1225 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.3
DANN	Benign	0.23
PhyloP100		0.61
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: rs1171267; hg19: chr1-66003854;