rs41457646

chr7-128256968-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.*2205G>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 0.114 in 152,552 control chromosomes in the GnomAD database, including 1,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1326 hom., cov: 32)
  • Exomes 𝑓: 0.11 (2 hom.)
• Consequence: LEP NM_000230.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.00100

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=-0.85).
• BP6: Variant 7-128256968-G-A is Benign according to our data. Variant chr7-128256968-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 358842.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.*2205G>A		3_prime_UTR_variant	3/3	ENST00000308868.5
LEP	XM_005250340.6	c.*2205G>A		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.*2205G>A		3_prime_UTR_variant	3/3	1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17295 AN: 152106 Hom.: 1325 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0997

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.113 AC: 37 AN: 328 Hom.: 2 Cov.: 0 AF XY: 0.115 AC XY: 22 AN XY: 192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.0600

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.114 AC: 17302 AN: 152224 Hom.: 1326 Cov.: 32 AF XY: 0.116 AC XY: 8609 AN XY: 74412

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.0997

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.119

Alfa AF: 0.123 Hom.: 303

Bravo AF: 0.112

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.74
Dann	Benign	0.41

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: rs41457646; hg19: chr7-127897021;