7-128244336-C-T

Variant names:

• chr7-128244336-C-T
• rs4731427
• NM_000230.3:c.-29+3030C>T

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+3030C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 152,080 control chromosomes in the GnomAD database, including 63,261 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 0.91 (63261 hom., cov: 30)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.539
• Publications: 13 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.944 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.-29+3030C>T		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.-29+3030C>T		intron	N/A	ENSP00000312652.4	P41159
	LEP	ENST00000965599.1		c.-29+3030C>T		intron	N/A	ENSP00000635658.1
	ENSG00000289434	ENST00000785131.1		n.168+19026G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.911 AC: 138414 AN: 151962 Hom.: 63215 Cov.: 30

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.967

Gnomad FIN AF: 0.925

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.923

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

GnomAD4 genome AF: 0.911 AC: 138516 AN: 152080 Hom.: 63261 Cov.: 30 AF XY: 0.913 AC XY: 67849 AN XY: 74318

African (AFR) AF: 0.841 AC: 34868 AN: 41446

American (AMR) AF: 0.945 AC: 14445 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 3165 AN: 3472

East Asian (EAS) AF: 0.946 AC: 4878 AN: 5158

South Asian (SAS) AF: 0.967 AC: 4659 AN: 4818

European-Finnish (FIN) AF: 0.925 AC: 9774 AN: 10564

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63588 AN: 68026

Other (OTH) AF: 0.924 AC: 1945 AN: 2106

Alfa AF: 0.929 Hom.: 74363

Bravo AF: 0.910

Asia WGS AF: 0.950 AC: 3303 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.8
DANN	Benign	0.65
PhyloP100		0.54
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: rs4731427; hg19: chr7-127884389;