rs3790438

Variant names:

• chr1-65619842-T-A
• rs3790438
• NM_002303.6:c.2396-86T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-65619842-T-A
• chr1-65619842-T-G

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.2396-86T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,018,134 control chromosomes in the GnomAD database, including 15,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2485 hom., cov: 32)
  • Exomes 𝑓: 0.17 (12759 hom.)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.902
• Publications: 16 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=-0.86).
• BP6: Variant 1-65619842-T-A is Benign according to our data. Variant chr1-65619842-T-A is described in ClinVar as Benign. ClinVar VariationId is 1247474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.2396-86T>A		intron_variant	Intron 16 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.2396-86T>A		intron_variant	Intron 16 of 19	1	NM_002303.6	ENSP00000330393.7

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26614 AN: 152082 Hom.: 2485 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0600

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.168 AC: 145642 AN: 865934 Hom.: 12759 AF XY: 0.168 AC XY: 75824 AN XY: 450020

African (AFR) AF: 0.194 AC: 3997 AN: 20618

American (AMR) AF: 0.175 AC: 6508 AN: 37282

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 4641 AN: 21304

East Asian (EAS) AF: 0.0821 AC: 2763 AN: 33646

South Asian (SAS) AF: 0.146 AC: 9786 AN: 66962

European-Finnish (FIN) AF: 0.123 AC: 6128 AN: 49874

Middle Eastern (MID) AF: 0.266 AC: 847 AN: 3188

European-Non Finnish (NFE) AF: 0.176 AC: 104103 AN: 593132

Other (OTH) AF: 0.172 AC: 6869 AN: 39928

GnomAD4 genome AF: 0.175 AC: 26627 AN: 152200 Hom.: 2485 Cov.: 32 AF XY: 0.173 AC XY: 12846 AN XY: 74410

African (AFR) AF: 0.192 AC: 7960 AN: 41524

American (AMR) AF: 0.206 AC: 3143 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 767 AN: 3472

East Asian (EAS) AF: 0.0604 AC: 313 AN: 5184

South Asian (SAS) AF: 0.127 AC: 615 AN: 4824

European-Finnish (FIN) AF: 0.125 AC: 1327 AN: 10602

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11843 AN: 67990

Other (OTH) AF: 0.176 AC: 373 AN: 2116

Alfa AF: 0.160 Hom.: 257

Bravo AF: 0.179

Asia WGS AF: 0.0970 AC: 335 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		0.90
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3790438; hg19: chr1-66085525; COSMIC: COSV60750180; COSMIC: COSV60750180;