rs17151922

Positions:

• chr7-128255163-G-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEP	NM_000230.3	c.*400G>T		3_prime_UTR_variant	3/3	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.*400G>T		3_prime_UTR_variant	3/3		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.*400G>T		3_prime_UTR_variant	3/3	1	NM_000230.3	ENSP00000312652.4

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

Gnomad4 AFR exome AF: 0.274

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0232

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.0242

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

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.0398

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0220

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.0733

Alfa AF: 0.0310 Hom.: 392

Bravo AF: 0.0970

Asia WGS AF: 0.0310 AC: 111 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic Non-Syndromic Obesity Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Obesity due to congenital leptin deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs17151922; hg19: chr7-127895216;