NM_000230.3:c.145-573A>G

Variant names:

• chr7-128253831-A-G
• rs7788818
• NM_000230.3:c.145-573A>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.145-573A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.925 in 152,322 control chromosomes in the GnomAD database, including 65,233 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 0.92 (65233 hom., cov: 34)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.261
• 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: 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	NM_000230.3	MANE Select	c.145-573A>G		intron	N/A	NP_000221.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	ENST00000308868.5	TSL:1 MANE Select	c.145-573A>G		intron	N/A	ENSP00000312652.4
	ENSG00000289434	ENST00000785131.1		n.168+9531T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140740 AN: 152204 Hom.: 65186 Cov.: 34

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.988

Gnomad AMR AF: 0.954

Gnomad ASJ AF: 0.950

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.987

Gnomad FIN AF: 0.926

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.936

Gnomad OTH AF: 0.944

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

GnomAD4 genome AF: 0.925 AC: 140845 AN: 152322 Hom.: 65233 Cov.: 34 AF XY: 0.927 AC XY: 69031 AN XY: 74482

African (AFR) AF: 0.874 AC: 36310 AN: 41566

American (AMR) AF: 0.954 AC: 14600 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3298 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5184 AN: 5192

South Asian (SAS) AF: 0.986 AC: 4765 AN: 4832

European-Finnish (FIN) AF: 0.926 AC: 9816 AN: 10602

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.936 AC: 63689 AN: 68030

Other (OTH) AF: 0.945 AC: 1995 AN: 2112

Alfa AF: 0.933 Hom.: 45022

Bravo AF: 0.924

Asia WGS AF: 0.987 AC: 3434 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.66
DANN	Benign	0.26
PhyloP100		-0.26
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: rs7788818; hg19: chr7-127893884;