1-65592830-A-T

Position:

• chr1-65592830-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002303.6(LEPR):​c.668A>T​(p.Gln223Leu) 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. 13/21 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. Q223R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16019481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.668A>T	p.Gln223Leu	missense_variant	6/20	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.668A>T	p.Gln223Leu	missense_variant	6/20	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;T;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;.;T;T;T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.4	N;N;N;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.38	T;T;T;T;.;T
Sift4G	Benign	0.084	T;T;T;T;T;T
Polyphen		0.83	P;B;B;.;B;.
Vest4		0.45
MutPred		0.44		Gain of stability (P = 0.0242);Gain of stability (P = 0.0242);Gain of stability (P = 0.0242);Gain of stability (P = 0.0242);Gain of stability (P = 0.0242);Gain of stability (P = 0.0242);
MVP		0.62
MPC		0.12
ClinPred		0.44	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs1137101; hg19: chr1-66058513;