rs1800564

chr7-128254587-G-Achr7-128254587-G-Cchr7-128254587-G-T

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>A(p.Val110Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: LEP NM_000230.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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=0.06650892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEP	NM_000230.3	c.328G>A	p.Val110Met	missense_variant	3/3	ENST00000308868.5
LEP	XM_005250340.6	c.325G>A	p.Val109Met	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEP	ENST00000308868.5	c.328G>A	p.Val110Met	missense_variant	3/3	1	NM_000230.3	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251460 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.000151 AC XY: 110 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LEP-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2023

The LEP c.328G>A variant is predicted to result in the amino acid substitution p.Val110Met. This variant was reported in the heterozygous state in an obese individual with a low serum leptin level (Karvonen et al. 1998. PubMed ID: 9745435). This variant was also documented in the heterozygous state in a control individual with normal weight (Echwald et al. 1997. PubMed ID: 9130031). This variant is also reported in 0.036% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-127894640-G-A), which is a much higher frequency than other documented causative variants in this gene (Human Gene Mutation Database). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 110 of the LEP protein (p.Val110Met). This variant is present in population databases (rs1800564, gnomAD 0.03%). This missense change has been observed in individual(s) with obesity (PMID: 9745435). ClinVar contains an entry for this variant (Variation ID: 2136611). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.5
Dann	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.033	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Uncertain	0.019	D
Polyphen		0.0050	B
Vest4		0.028
MVP		0.61
MPC		0.52
ClinPred		0.018	T
GERP RS		2.5
Varity_R		0.11
gMVP		0.21

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;