7-128254252-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000230.3(LEP):c.145-152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 909,420 control chromosomes in the GnomAD database, including 93,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (12628 hom., cov: 32)
  • Exomes 𝑓: 0.45 (80917 hom.)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.54

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-128254252-G-A is Benign according to our data. Variant chr7-128254252-G-A is described in ClinVar as [Benign]. Clinvar id is 1247016.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.145-152G>A		intron_variant		ENST00000308868.5
LEP	XM_005250340.6	c.145-155G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.145-152G>A		intron_variant		1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58183 AN: 151892 Hom.: 12620 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.450 AC: 340882 AN: 757412 Hom.: 80917 AF XY: 0.455 AC XY: 181354 AN XY: 398366

Gnomad4 AFR exome AF: 0.183

Gnomad4 AMR exome AF: 0.411

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.761

Gnomad4 SAS exome AF: 0.519

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.433

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.383 AC: 58212 AN: 152008 Hom.: 12628 Cov.: 32 AF XY: 0.391 AC XY: 29015 AN XY: 74292

Gnomad4 AFR AF: 0.187

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.735

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.462

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.389

Alfa AF: 0.410 Hom.: 3569

Bravo AF: 0.369

Asia WGS AF: 0.623 AC: 2163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.0050
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3828942; hg19: chr7-127894305; COSMIC: COSV58240657;