7-128242017-G-C

Variant names:

• chr7-128242017-G-C
• rs4731426
• NM_000230.3:c.-29+711G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000230.3(LEP):​c.-29+711G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 152,150 control chromosomes in the GnomAD database, including 17,863 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (17863 hom., cov: 33)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 32 publications found

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]

LEP Gene-Disease associations (from GenCC):

• obesity due to congenital leptin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ENSG00000289434 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.-29+711G>C		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.-29+711G>C		intron_variant	Intron 1 of 2		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.-29+711G>C		intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1	n.169-20477C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67531 AN: 152032 Hom.: 17859 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.528

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.474

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.444 AC: 67548 AN: 152150 Hom.: 17863 Cov.: 33 AF XY: 0.452 AC XY: 33597 AN XY: 74396

African (AFR) AF: 0.140 AC: 5801 AN: 41526

American (AMR) AF: 0.513 AC: 7841 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 1833 AN: 3472

East Asian (EAS) AF: 0.745 AC: 3862 AN: 5182

South Asian (SAS) AF: 0.603 AC: 2902 AN: 4816

European-Finnish (FIN) AF: 0.561 AC: 5937 AN: 10580

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.553 AC: 37612 AN: 67974

Other (OTH) AF: 0.477 AC: 1008 AN: 2112

Alfa AF: 0.334 Hom.: 1000

Bravo AF: 0.423

Asia WGS AF: 0.654 AC: 2270 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.50
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4731426; hg19: chr7-127882070;