chr1-65623018-C-A

Variant names:

• chr1-65623018-C-A
• rs12067936
• NM_002303.6:c.2673+37C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002303.6(LEPR):​c.2673+37C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,592,948 control chromosomes in the GnomAD database, including 140,401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17186 hom., cov: 32)
  • Exomes 𝑓: 0.40 (123215 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0660
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-65623018-C-A is Benign according to our data. Variant chr1-65623018-C-A is described in ClinVar as Benign. ClinVar VariationId is 1183122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2673+37C>A		intron_variant	Intron 19 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2673+37C>A		intron_variant	Intron 19 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70255 AN: 151780 Hom.: 17149 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.491

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.464 AC: 111844 AN: 240932 AF XY: 0.457

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.514

Gnomad ASJ exome AF: 0.370

Gnomad EAS exome AF: 0.872

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.427

GnomAD4 exome AF: 0.403 AC: 581230 AN: 1441050 Hom.: 123215 Cov.: 27 AF XY: 0.403 AC XY: 289389 AN XY: 717494

African (AFR) AF: 0.551 AC: 18270 AN: 33134

American (AMR) AF: 0.506 AC: 22300 AN: 44080

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 9749 AN: 25914

East Asian (EAS) AF: 0.868 AC: 34311 AN: 39522

South Asian (SAS) AF: 0.464 AC: 39569 AN: 85312

European-Finnish (FIN) AF: 0.473 AC: 25028 AN: 52948

Middle Eastern (MID) AF: 0.361 AC: 1991 AN: 5510

European-Non Finnish (NFE) AF: 0.370 AC: 405106 AN: 1095010

Other (OTH) AF: 0.418 AC: 24906 AN: 59620

GnomAD4 genome AF: 0.463 AC: 70348 AN: 151898 Hom.: 17186 Cov.: 32 AF XY: 0.470 AC XY: 34912 AN XY: 74202

African (AFR) AF: 0.550 AC: 22763 AN: 41408

American (AMR) AF: 0.485 AC: 7401 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1301 AN: 3470

East Asian (EAS) AF: 0.869 AC: 4500 AN: 5178

South Asian (SAS) AF: 0.462 AC: 2228 AN: 4822

European-Finnish (FIN) AF: 0.491 AC: 5164 AN: 10512

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25652 AN: 67940

Other (OTH) AF: 0.442 AC: 931 AN: 2108

Alfa AF: 0.411 Hom.: 6537

Bravo AF: 0.465

Asia WGS AF: 0.626 AC: 2175 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.8
DANN	Benign	0.60
PhyloP100		0.066
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12067936; hg19: chr1-66088701; COSMIC: COSV60750252;