1-65593118-A-G

Position:

• chr1-65593118-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002303.6(LEPR):​c.703+253A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 151,906 control chromosomes in the GnomAD database, including 32,571 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.65 (32571 hom., cov: 32)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.522

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 1-65593118-A-G is Benign according to our data. Variant chr1-65593118-A-G is described in ClinVar as [Benign]. Clinvar id is 1286120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.703+253A>G		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.703+253A>G		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98857 AN: 151788 Hom.: 32526 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.642

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

GnomAD4 genome AF: 0.651 AC: 98959 AN: 151906 Hom.: 32571 Cov.: 32 AF XY: 0.656 AC XY: 48727 AN XY: 74242

Gnomad4 AFR AF: 0.607

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.924

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.725

Gnomad4 NFE AF: 0.644

Gnomad4 OTH AF: 0.646

Alfa AF: 0.636 Hom.: 39609

Bravo AF: 0.640

Asia WGS AF: 0.795 AC: 2759 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.79
DANN	Benign	0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs4655537; hg19: chr1-66058801; COSMIC: COSV60749969;