chr7-128243642-T-A

Variant names:

• chr7-128243642-T-A
• rs4236625
• NM_000230.3:c.-29+2336T>A

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+2336T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.906 in 152,202 control chromosomes in the GnomAD database, including 62,667 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 (62667 hom., cov: 32)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.282

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.-29+2336T>A		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.-29+2336T>A		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+2336T>A		intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4

Frequencies

GnomAD3 genomes AF: 0.906 AC: 137759 AN: 152084 Hom.: 62621 Cov.: 32

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.943

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.927

Gnomad FIN AF: 0.926

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.921

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

GnomAD4 genome AF: 0.906 AC: 137861 AN: 152202 Hom.: 62667 Cov.: 32 AF XY: 0.908 AC XY: 67540 AN XY: 74418

African (AFR) AF: 0.828 AC: 34370 AN: 41504

American (AMR) AF: 0.943 AC: 14441 AN: 15308

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

East Asian (EAS) AF: 0.946 AC: 4895 AN: 5176

South Asian (SAS) AF: 0.926 AC: 4465 AN: 4820

European-Finnish (FIN) AF: 0.926 AC: 9815 AN: 10602

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63568 AN: 68000

Other (OTH) AF: 0.921 AC: 1947 AN: 2114

Alfa AF: 0.916 Hom.: 7948

Bravo AF: 0.906

Asia WGS AF: 0.936 AC: 3255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.7
DANN	Benign	0.80
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

Publications

LitVar

Other links and lift over

dbSNP: rs4236625; hg19: chr7-127883695;