chr1-65572246-C-G

Position:

• chr1-65572246-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002303.6(LEPR):​c.371-80C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,397,890 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (98 hom., cov: 29)
  • Exomes 𝑓: 0.012 (619 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.31

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-65572246-C-G is Benign according to our data. Variant chr1-65572246-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1222942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.371-80C>G		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.371-80C>G		intron_variant		1	NM_002303.6	P4

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 1996 AN: 131628 Hom.: 97 Cov.: 29

Gnomad AFR AF: 0.00346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00501

Gnomad ASJ AF: 0.000615

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.00855

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.0166

GnomAD4 exome AF: 0.0118 AC: 14954 AN: 1266224 Hom.: 619 AF XY: 0.0114 AC XY: 7119 AN XY: 623906

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.000473

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.00389

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.00677

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0151 AC: 1994 AN: 131666 Hom.: 98 Cov.: 29 AF XY: 0.0176 AC XY: 1113 AN XY: 63214

Gnomad4 AFR AF: 0.00346

Gnomad4 AMR AF: 0.00501

Gnomad4 ASJ AF: 0.000615

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.00833

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.00728

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00953 Hom.: 5

Bravo AF: 0.0119

Asia WGS AF: 0.0870 AC: 298 AN: 3442

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.67

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: rs13306519; hg19: chr1-66037929;