rs17412175

Variant names:

• chr1-65439203-T-A
• rs17412175
• NM_002303.6:c.-21+13825T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65439203-T-A
• chr1-65439203-T-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.-21+13825T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,122 control chromosomes in the GnomAD database, including 9,565 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 0.32 (9565 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 14 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.-21+13825T>A		intron_variant	Intron 2 of 19	ENST00000349533.11	NP_002294.2
LEPR	NM_001003680.3	c.-21+13825T>A		intron_variant	Intron 2 of 19		NP_001003680.1
LEPR	NM_001003679.3	c.-21+13825T>A		intron_variant	Intron 2 of 19		NP_001003679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+13825T>A		intron_variant	Intron 2 of 19	1	NM_002303.6	ENSP00000330393.7
LEPR	ENST00000371059.7	c.-21+13825T>A		intron_variant	Intron 2 of 19	1		ENSP00000360098.3
LEPR	ENST00000371060.7	c.-21+13825T>A		intron_variant	Intron 2 of 19	1		ENSP00000360099.3

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47997 AN: 152002 Hom.: 9568 Cov.: 32

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.381

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.316 AC: 47995 AN: 152122 Hom.: 9565 Cov.: 32 AF XY: 0.310 AC XY: 23023 AN XY: 74352

African (AFR) AF: 0.0912 AC: 3788 AN: 41536

American (AMR) AF: 0.365 AC: 5582 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1638 AN: 3472

East Asian (EAS) AF: 0.0284 AC: 147 AN: 5170

South Asian (SAS) AF: 0.318 AC: 1536 AN: 4826

European-Finnish (FIN) AF: 0.367 AC: 3872 AN: 10548

Middle Eastern (MID) AF: 0.372 AC: 108 AN: 290

European-Non Finnish (NFE) AF: 0.444 AC: 30190 AN: 67980

Other (OTH) AF: 0.359 AC: 757 AN: 2110

Alfa AF: 0.250 Hom.: 672

Bravo AF: 0.307

Asia WGS AF: 0.192 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.5
DANN	Benign	0.67
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17412175; hg19: chr1-65904886;