chr7-128250098-A-G

Variant names:

• chr7-128250098-A-G
• rs7795794
• NM_000230.3:c.-28-1893A>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.-28-1893A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 152,206 control chromosomes in the GnomAD database, including 65,162 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 (65162 hom., cov: 31)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.03
• Publications: 12 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=-0.88).
• 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.-28-1893A>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.-28-1893A>G		intron	N/A	ENSP00000312652.4
	ENSG00000289434	ENST00000785131.1		n.168+13264T>C		intron	N/A
	ENSG00000302259	ENST00000785222.1		n.236-581A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.925 AC: 140606 AN: 152088 Hom.: 65114 Cov.: 31

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: 0.924 AC: 140712 AN: 152206 Hom.: 65162 Cov.: 31 AF XY: 0.926 AC XY: 68945 AN XY: 74416

African (AFR) AF: 0.873 AC: 36217 AN: 41494

American (AMR) AF: 0.954 AC: 14591 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.950 AC: 3296 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5168 AN: 5176

South Asian (SAS) AF: 0.986 AC: 4760 AN: 4826

European-Finnish (FIN) AF: 0.926 AC: 9814 AN: 10600

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

European-Non Finnish (NFE) AF: 0.936 AC: 63681 AN: 68024

Other (OTH) AF: 0.944 AC: 1997 AN: 2116

Alfa AF: 0.934 Hom.: 82603

Bravo AF: 0.924

Asia WGS AF: 0.987 AC: 3433 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	0.45
DANN	Benign	0.72
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7795794; hg19: chr7-127890151;