7-128254297-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000230.3(LEP):c.145-107G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,454,758 control chromosomes in the GnomAD database, including 1,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (150 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1265 hom.)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.579

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=-0.78).
• BP6: Variant 7-128254297-G-A is Benign according to our data. Variant chr7-128254297-G-A is described in ClinVar as [Benign]. Clinvar id is 1294302.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0331 (5046/152256) while in subpopulation NFE AF= 0.0491 (3341/68018). AF 95% confidence interval is 0.0477. There are 150 homozygotes in gnomad4. There are 2466 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 150 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.145-107G>A		intron_variant		ENST00000308868.5
LEP	XM_005250340.6	c.145-110G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.145-107G>A		intron_variant		1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5050 AN: 152140 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.00860

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.0405 AC: 52717 AN: 1302502 Hom.: 1265 AF XY: 0.0396 AC XY: 25956 AN XY: 655718

Gnomad4 AFR exome AF: 0.00610

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0609

Gnomad4 NFE exome AF: 0.0464

Gnomad4 OTH exome AF: 0.0365

GnomAD4 genome AF: 0.0331 AC: 5046 AN: 152256 Hom.: 150 Cov.: 32 AF XY: 0.0331 AC XY: 2466 AN XY: 74442

Gnomad4 AFR AF: 0.00857

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0706

Gnomad4 NFE AF: 0.0491

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0430 Hom.: 37

Bravo AF: 0.0277

Asia WGS AF: 0.00433 AC: 15 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 24, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	6.2
Dann	Benign	0.75

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: rs28954111; hg19: chr7-127894350;