rs13306517

chr7-128252093-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000230.3(LEP):c.75A>G(p.Gln25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,614,158 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (110 hom.)
• Consequence: LEP NM_000230.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.815

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-128252093-A-G is Benign according to our data. Variant chr7-128252093-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 778362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.815 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0057 (868/152284) while in subpopulation EAS AF= 0.0513 (265/5170). AF 95% confidence interval is 0.0462. There are 16 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.75A>G	p.Gln25=	synonymous_variant	2/3	ENST00000308868.5
LEP	XM_005250340.6	c.75A>G	p.Gln25=	synonymous_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.75A>G	p.Gln25=	synonymous_variant	2/3	1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152166 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00775 AC: 1949 AN: 251488 Hom.: 36 AF XY: 0.00791 AC XY: 1075 AN XY: 135916

Gnomad AFR exome AF: 0.00732

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0446

Gnomad SAS exome AF: 0.0161

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00381 AC: 5567 AN: 1461874 Hom.: 110 Cov.: 32 AF XY: 0.00419 AC XY: 3044 AN XY: 727240

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000605

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152284 Hom.: 16 Cov.: 32 AF XY: 0.00603 AC XY: 449 AN XY: 74470

Gnomad4 AFR AF: 0.00686

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.0513

Gnomad4 SAS AF: 0.0187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00358 Hom.: 4

Bravo AF: 0.00540

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	2.6
Dann	Benign	0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13306517; hg19: chr7-127892146;