rs17151922

Variant names:

• chr7-128255163-G-T
• rs17151922
• NM_000230.3:c.*400G>T

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.*400G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0678 in 223,564 control chromosomes in the GnomAD database, including 1,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1582 hom., cov: 32)
  • Exomes 𝑓: 0.026 (150 hom.)
• Consequence: LEP NM_000230.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.11
• Publications: 7 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=-0.81).
• BP6: Variant 7-128255163-G-T is Benign according to our data. Variant chr7-128255163-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 358827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 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.*400G>T		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.*400G>T		3_prime_UTR	Exon 3 of 3	ENSP00000312652.4	P41159
	LEP	ENST00000965599.1		c.*400G>T		3_prime_UTR	Exon 3 of 3	ENSP00000635658.1
	ENSG00000289434	ENST00000785131.1		n.168+8199C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13248 AN: 151966 Hom.: 1574 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0220

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0741

GnomAD4 exome AF: 0.0262 AC: 1875 AN: 71480 Hom.: 150 Cov.: 0 AF XY: 0.0256 AC XY: 948 AN XY: 37052

African (AFR) AF: 0.274 AC: 906 AN: 3306

American (AMR) AF: 0.0275 AC: 132 AN: 4808

Ashkenazi Jewish (ASJ) AF: 0.0269 AC: 50 AN: 1856

East Asian (EAS) AF: 0.00 AC: 0 AN: 4882

South Asian (SAS) AF: 0.0232 AC: 196 AN: 8444

European-Finnish (FIN) AF: 0.0153 AC: 34 AN: 2226

Middle Eastern (MID) AF: 0.0488 AC: 12 AN: 246

European-Non Finnish (NFE) AF: 0.0108 AC: 455 AN: 41996

Other (OTH) AF: 0.0242 AC: 90 AN: 3716

GnomAD4 genome AF: 0.0874 AC: 13285 AN: 152084 Hom.: 1582 Cov.: 32 AF XY: 0.0848 AC XY: 6302 AN XY: 74346

African (AFR) AF: 0.273 AC: 11300 AN: 41436

American (AMR) AF: 0.0398 AC: 609 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4826

European-Finnish (FIN) AF: 0.0220 AC: 233 AN: 10582

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0106 AC: 722 AN: 67996

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0586 Hom.: 1450

Bravo AF: 0.0970

Asia WGS AF: 0.0310 AC: 111 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.81
CADD	Benign	2.1
DANN	Benign	0.73
PhyloP100		1.1
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: rs17151922; hg19: chr7-127895216;