7-128254587-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000230.3(LEP):c.328G>C(p.Val110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V110M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LEP NM_000230.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.227

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain Leptin (size 145) in uniprot entity LEP_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000230.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053645343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.328G>C	p.Val110Leu	missense_variant	3/3	ENST00000308868.5
LEP	XM_005250340.6	c.325G>C	p.Val109Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.328G>C	p.Val110Leu	missense_variant	3/3	1	NM_000230.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.92
Dann	Benign	0.16
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.7	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MutPred		0.38		Loss of ubiquitination at K115 (P = 0.1216);
MVP		0.46
MPC		0.50
ClinPred		0.055	T
GERP RS		2.5
Varity_R		0.14
gMVP		0.26

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: rs1800564; hg19: chr7-127894640;