rs11761556

Variant names:

• chr7-128257016-C-A
• rs11761556
• NM_000230.3:c.*2253C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-128257016-C-A
• chr7-128257016-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000230.3(LEP):​c.*2253C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 152,118 control chromosomes in the GnomAD database, including 17,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (17279 hom., cov: 31)
  • Exomes 𝑓: 0.54 (40 hom.)
• Consequence: LEP NM_000230.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0650
• Publications: 27 publications found

Genes affected

LEP (HGNC:6553): (leptin) This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]

LEP Gene-Disease associations (from GenCC):

• obesity due to congenital leptin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000289434 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 7-128257016-C-A is Benign according to our data. Variant chr7-128257016-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 358845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000230.3. 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
	LEP	NM_000230.3	MANE Select	c.*2253C>A		3_prime_UTR	Exon 3 of 3	NP_000221.1	P41159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	ENST00000308868.5	TSL:1 MANE Select	c.*2253C>A		3_prime_UTR	Exon 3 of 3	ENSP00000312652.4	P41159
	ENSG00000289434	ENST00000785131.1		n.168+6346G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67401 AN: 151726 Hom.: 17271 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.732

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.483

GnomAD4 exome AF: 0.540 AC: 148 AN: 274 Hom.: 40 Cov.: 0 AF XY: 0.531 AC XY: 86 AN XY: 162

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.750 AC: 3 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.750 AC: 3 AN: 4

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.509 AC: 59 AN: 116

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.578 AC: 67 AN: 116

Other (OTH) AF: 0.462 AC: 12 AN: 26

GnomAD4 genome AF: 0.444 AC: 67426 AN: 151844 Hom.: 17279 Cov.: 31 AF XY: 0.448 AC XY: 33223 AN XY: 74210

African (AFR) AF: 0.175 AC: 7265 AN: 41428

American (AMR) AF: 0.517 AC: 7880 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1927 AN: 3460

East Asian (EAS) AF: 0.733 AC: 3776 AN: 5150

South Asian (SAS) AF: 0.578 AC: 2780 AN: 4810

European-Finnish (FIN) AF: 0.495 AC: 5213 AN: 10530

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36811 AN: 67900

Other (OTH) AF: 0.489 AC: 1030 AN: 2108

Alfa AF: 0.476 Hom.: 7080

Bravo AF: 0.429

Asia WGS AF: 0.648 AC: 2251 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	not provided (1)
-	-	1	Obesity due to congenital leptin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.85
DANN	Benign	0.50
PhyloP100		-0.065
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: rs11761556; hg19: chr7-127897069;