7-128247015-T-G

Variant names:

• chr7-128247015-T-G
• rs12706831
• NM_000230.3:c.-28-4976T>G

Variant summary

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

The NM_000230.3(LEP):​c.-28-4976T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,968 control chromosomes in the GnomAD database, including 16,907 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 0.43 (16907 hom., cov: 32)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 3 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000230.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	NM_000230.3	MANE Select	c.-28-4976T>G		intron	N/A	NP_000221.1	P41159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	ENST00000308868.5	TSL:1 MANE Select	c.-28-4976T>G		intron	N/A	ENSP00000312652.4	P41159
	LEP	ENST00000965599.1		c.-28-4976T>G		intron	N/A	ENSP00000635658.1
	ENSG00000289434	ENST00000785131.1		n.168+16347A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64816 AN: 151850 Hom.: 16906 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.733

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.522

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.460

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

GnomAD4 genome AF: 0.426 AC: 64811 AN: 151968 Hom.: 16907 Cov.: 32 AF XY: 0.432 AC XY: 32080 AN XY: 74244

African (AFR) AF: 0.112 AC: 4625 AN: 41466

American (AMR) AF: 0.508 AC: 7766 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1852 AN: 3468

East Asian (EAS) AF: 0.733 AC: 3783 AN: 5158

South Asian (SAS) AF: 0.560 AC: 2706 AN: 4832

European-Finnish (FIN) AF: 0.522 AC: 5490 AN: 10510

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36863 AN: 67942

Other (OTH) AF: 0.463 AC: 977 AN: 2110

Alfa AF: 0.294 Hom.: 1005

Bravo AF: 0.409

Asia WGS AF: 0.633 AC: 2199 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.0
DANN	Benign	0.78
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: rs12706831; hg19: chr7-127887068;