rs3828033

Variant names:

• chr1-65599027-C-T
• rs3828033
• NM_002303.6:c.994+223C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-65599027-C-T
• chr1-65599027-C-A
• chr1-65599027-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002303.6(LEPR):​c.994+223C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,872 control chromosomes in the GnomAD database, including 16,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (16809 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.619
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-65599027-C-T is Benign according to our data. Variant chr1-65599027-C-T is described in ClinVar as Benign. ClinVar VariationId is 1236987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 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.994+223C>T		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.994+223C>T		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.994+223C>T		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.994+223C>T		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.994+223C>T		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.994+223C>T		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68656 AN: 151754 Hom.: 16776 Cov.: 31

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.419

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

GnomAD4 genome AF: 0.453 AC: 68735 AN: 151872 Hom.: 16809 Cov.: 31 AF XY: 0.461 AC XY: 34211 AN XY: 74210

African (AFR) AF: 0.547 AC: 22637 AN: 41398

American (AMR) AF: 0.395 AC: 6031 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1257 AN: 3468

East Asian (EAS) AF: 0.874 AC: 4517 AN: 5166

South Asian (SAS) AF: 0.441 AC: 2123 AN: 4818

European-Finnish (FIN) AF: 0.555 AC: 5845 AN: 10538

Middle Eastern (MID) AF: 0.317 AC: 92 AN: 290

European-Non Finnish (NFE) AF: 0.371 AC: 25179 AN: 67926

Other (OTH) AF: 0.426 AC: 898 AN: 2106

Alfa AF: 0.368 Hom.: 2807

Bravo AF: 0.446

Asia WGS AF: 0.654 AC: 2270 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.36
DANN	Benign	0.42
PhyloP100		-0.62
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: rs3828033; hg19: chr1-66064710;