rs970467

Variant names:

• chr1-65441079-C-T
• rs970467
• NM_002303.6:c.-21+15701C>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.-21+15701C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,184 control chromosomes in the GnomAD database, including 1,948 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 0.15 (1948 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 17 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+15701C>T		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+15701C>T		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+15701C>T		intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+15701C>T		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+15701C>T		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+15701C>T		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23096 AN: 152066 Hom.: 1942 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0665

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.141

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

GnomAD4 genome AF: 0.152 AC: 23120 AN: 152184 Hom.: 1948 Cov.: 32 AF XY: 0.151 AC XY: 11218 AN XY: 74400

African (AFR) AF: 0.222 AC: 9220 AN: 41502

American (AMR) AF: 0.171 AC: 2620 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3472

East Asian (EAS) AF: 0.114 AC: 589 AN: 5184

South Asian (SAS) AF: 0.216 AC: 1038 AN: 4816

European-Finnish (FIN) AF: 0.0665 AC: 704 AN: 10592

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8157 AN: 68002

Other (OTH) AF: 0.142 AC: 299 AN: 2112

Alfa AF: 0.135 Hom.: 4712

Bravo AF: 0.162

Asia WGS AF: 0.169 AC: 594 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.50
PhyloP100		1.6
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: rs970467; hg19: chr1-65906762;