1-65437762-A-T

Variant names:

• chr1-65437762-A-T
• rs17097182
• NM_002303.6:c.-21+12384A>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+12384A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,064 control chromosomes in the GnomAD database, including 2,078 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 0.12 (2078 hom., cov: 30)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 9 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-21+12384A>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.-21+12384A>T		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001003679.3		c.-21+12384A>T		intron	N/A	NP_001003679.1	P48357-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+12384A>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.-21+12384A>T		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000371060.7	TSL:1	c.-21+12384A>T		intron	N/A	ENSP00000360099.3	P48357-2

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18305 AN: 151946 Hom.: 2072 Cov.: 30

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0575

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.0250

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.121 AC: 18333 AN: 152064 Hom.: 2078 Cov.: 30 AF XY: 0.120 AC XY: 8896 AN XY: 74364

African (AFR) AF: 0.296 AC: 12288 AN: 41444

American (AMR) AF: 0.0573 AC: 875 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3466

East Asian (EAS) AF: 0.0249 AC: 128 AN: 5144

South Asian (SAS) AF: 0.0944 AC: 455 AN: 4820

European-Finnish (FIN) AF: 0.0711 AC: 753 AN: 10592

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0491 AC: 3338 AN: 68004

Other (OTH) AF: 0.110 AC: 232 AN: 2110

Alfa AF: 0.0295 Hom.: 27

Bravo AF: 0.125

Asia WGS AF: 0.0840 AC: 291 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.0
DANN	Benign	0.93
PhyloP100		0.32
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: rs17097182; hg19: chr1-65903445;