chr1-65430625-T-C

Variant names:

• chr1-65430625-T-C
• rs12065099
• NM_002303.6:c.-21+5247T>C

Variant summary

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

The NM_002303.6(LEPR):​c.-21+5247T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,214 control chromosomes in the GnomAD database, including 2,445 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 0.13 (2445 hom., cov: 33)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00900
• Publications: 5 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]

LEPROT (HGNC:29477): (leptin receptor overlapping transcript) LEPROT is associated with the Golgi complex and endosomes and has a role in cell surface expression of growth hormone receptor (GHR; MIM 600946) and leptin receptor (OBR, or LEPR; MIM 601007), thereby altering receptor-mediated cell signaling (Couturier et al., 2007 [PubMed 18042720]; Touvier et al., 2009 [PubMed 19907080]).[supplied by OMIM, Jul 2010]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.-21+5247T>C		intron	N/A	NP_002294.2
	LEPROT	NM_017526.5	MANE Select	c.279+577T>C		intron	N/A	NP_059996.1	O15243
	LEPR	NM_001003680.3		c.-21+5247T>C		intron	N/A	NP_001003680.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.-21+5247T>C		intron	N/A	ENSP00000330393.7	P48357-1
	LEPROT	ENST00000371065.9	TSL:1 MANE Select	c.279+577T>C		intron	N/A	ENSP00000360104.4	O15243
	LEPR	ENST00000371059.7	TSL:1	c.-21+5247T>C		intron	N/A	ENSP00000360098.3	P48357-3

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19802 AN: 152096 Hom.: 2438 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0629

Gnomad ASJ AF: 0.0645

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0507

Gnomad OTH AF: 0.118

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

GnomAD4 genome AF: 0.130 AC: 19838 AN: 152214 Hom.: 2445 Cov.: 33 AF XY: 0.129 AC XY: 9603 AN XY: 74426

African (AFR) AF: 0.326 AC: 13517 AN: 41460

American (AMR) AF: 0.0626 AC: 958 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0645 AC: 224 AN: 3472

East Asian (EAS) AF: 0.0268 AC: 139 AN: 5190

South Asian (SAS) AF: 0.0994 AC: 480 AN: 4828

European-Finnish (FIN) AF: 0.0711 AC: 755 AN: 10614

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0507 AC: 3449 AN: 68032

Other (OTH) AF: 0.118 AC: 248 AN: 2110

Alfa AF: 0.0754 Hom.: 1208

Bravo AF: 0.136

Asia WGS AF: 0.0890 AC: 308 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.58
PhyloP100		0.0090
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: rs12065099; hg19: chr1-65896308;