rs34499590

chr1-65616108-C-Gchr1-65616108-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002303.6(LEPR):c.2096C>G(p.Thr699Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T699M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.52

Genes affected

LEPR (HGNC:6554): (leptin receptor) The protein encoded by this gene belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight), and is involved in the regulation of fat metabolism, as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Mutations in this gene have been associated with obesity and pituitary dysfunction. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. It is noteworthy that this gene and LEPROT gene (GeneID:54741) share the same promoter and the first 2 exons, however, encode distinct proteins (PMID:9207021).[provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.2096C>G	p.Thr699Arg	missense_variant	15/20	ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.2096C>G	p.Thr699Arg	missense_variant	15/20	1	NM_002303.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	24
Dann	Uncertain	0.98
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;.
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	2.9	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D;D;D;D;.;D
REVEL	Uncertain	0.35
Sift	Benign	0.10	T;T;T;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.92
MutPred		0.48		Gain of methylation at K700 (P = 0.0624);Gain of methylation at K700 (P = 0.0624);Gain of methylation at K700 (P = 0.0624);Gain of methylation at K700 (P = 0.0624);Gain of methylation at K700 (P = 0.0624);Gain of methylation at K700 (P = 0.0624);
MVP		0.81
MPC		0.55
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.48
gMVP		0.76

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: rs34499590; hg19: chr1-66081791;