1-65596642-A-G

Position:

• chr1-65596642-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002303.6(LEPR):​c.849+49A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 1,554,048 control chromosomes in the GnomAD database, including 23,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1767 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21292 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-65596642-A-G is Benign according to our data. Variant chr1-65596642-A-G is described in ClinVar as [Benign]. Clinvar id is 1183725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEPR	NM_002303.6	c.849+49A>G		intron_variant		ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.849+49A>G		intron_variant		1	NM_002303.6	ENSP00000330393	P4

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20335 AN: 151848 Hom.: 1765 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.0403

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.155

GnomAD3 exomes AF: 0.155 AC: 36246 AN: 233978 Hom.: 3087 AF XY: 0.160 AC XY: 20401 AN XY: 127214

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.218

Gnomad EAS exome AF: 0.0343

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.169 AC: 237524 AN: 1402082 Hom.: 21292 Cov.: 24 AF XY: 0.171 AC XY: 119502 AN XY: 699882

Gnomad4 AFR exome AF: 0.0312

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.0616

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.134 AC: 20339 AN: 151966 Hom.: 1767 Cov.: 32 AF XY: 0.132 AC XY: 9836 AN XY: 74280

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.226

Gnomad4 EAS AF: 0.0406

Gnomad4 SAS AF: 0.154

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.153

Alfa AF: 0.150 Hom.: 1189

Bravo AF: 0.131

Asia WGS AF: 0.0960 AC: 332 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.0
DANN	Benign	0.81

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: rs3828034; hg19: chr1-66062325; COSMIC: COSV60749977;