1-65570758-A-T

Variant names:

• chr1-65570758-A-T
• rs1137100
• NM_002303.6:c.326A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002303.6(LEPR):​c.326A>T​(p.Lys109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K109R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LEPR NM_002303.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 358 publications found

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]

LEPR Gene-Disease associations (from GenCC):

• obesity due to leptin receptor gene deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.326A>T	p.Lys109Met	missense_variant	Exon 4 of 20	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.326A>T	p.Lys109Met	missense_variant	Exon 4 of 20	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 704746

African (AFR) AF: 0.00 AC: 0 AN: 32240

American (AMR) AF: 0.00 AC: 0 AN: 39682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.00 AC: 0 AN: 80806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092788

Other (OTH) AF: 0.00 AC: 0 AN: 58736

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;.;T;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D;.;D;D;D;.
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M
PhyloP100		2.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N;N;N;.;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.48
MutPred		0.46		Loss of solvent accessibility (P = 0.0045);Loss of solvent accessibility (P = 0.0045);Loss of solvent accessibility (P = 0.0045);Loss of solvent accessibility (P = 0.0045);Loss of solvent accessibility (P = 0.0045);Loss of solvent accessibility (P = 0.0045);
MVP		0.64
MPC		0.57
ClinPred		0.93	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.70
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs1137100; hg19: chr1-66036441;