NM_002303.6:c.1995+1611T>G

Variant names:

• chr1-65611907-T-G
• rs6690625
• NM_002303.6:c.1995+1611T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.1995+1611T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 152,184 control chromosomes in the GnomAD database, including 7,290 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (7290 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.732
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.1995+1611T>G		intron_variant	Intron 14 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.1995+1611T>G		intron_variant	Intron 14 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42939 AN: 152066 Hom.: 7277 Cov.: 33

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.253

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.282 AC: 42989 AN: 152184 Hom.: 7290 Cov.: 33 AF XY: 0.292 AC XY: 21742 AN XY: 74400

African (AFR) AF: 0.339 AC: 14078 AN: 41502

American (AMR) AF: 0.276 AC: 4221 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 536 AN: 3468

East Asian (EAS) AF: 0.809 AC: 4191 AN: 5180

South Asian (SAS) AF: 0.334 AC: 1613 AN: 4824

European-Finnish (FIN) AF: 0.365 AC: 3869 AN: 10590

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13806 AN: 68008

Other (OTH) AF: 0.261 AC: 553 AN: 2116

Alfa AF: 0.239 Hom.: 804

Bravo AF: 0.280

Asia WGS AF: 0.522 AC: 1813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.7
DANN	Benign	0.56
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs6690625; hg19: chr1-66077590;