1-65596642-A-G

Variant names:

• chr1-65596642-A-G
• rs3828034
• NM_002303.6:c.849+49A>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.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
• Publications: 22 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 1-65596642-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 rank	MANE	Protein	UniProt
LEPR	NM_002303.6	c.849+49A>G		intron_variant	Intron 7 of 19	ENST00000349533.11	NP_002294.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEPR	ENST00000349533.11	c.849+49A>G		intron_variant	Intron 7 of 19	1	NM_002303.6	ENSP00000330393.7

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

GnomAD2 exomes AF: 0.155 AC: 36246 AN: 233978 AF XY: 0.160

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 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

African (AFR) AF: 0.0312 AC: 999 AN: 32022

American (AMR) AF: 0.166 AC: 7238 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5667 AN: 25440

East Asian (EAS) AF: 0.0616 AC: 2405 AN: 39026

South Asian (SAS) AF: 0.168 AC: 14129 AN: 83942

European-Finnish (FIN) AF: 0.126 AC: 6595 AN: 52140

Middle Eastern (MID) AF: 0.250 AC: 1249 AN: 5004

European-Non Finnish (NFE) AF: 0.178 AC: 189672 AN: 1062672

Other (OTH) AF: 0.165 AC: 9570 AN: 58102

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

African (AFR) AF: 0.0353 AC: 1463 AN: 41490

American (AMR) AF: 0.191 AC: 2914 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 781 AN: 3460

East Asian (EAS) AF: 0.0406 AC: 210 AN: 5174

South Asian (SAS) AF: 0.154 AC: 741 AN: 4818

European-Finnish (FIN) AF: 0.128 AC: 1348 AN: 10548

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

European-Non Finnish (NFE) AF: 0.181 AC: 12269 AN: 67926

Other (OTH) AF: 0.153 AC: 322 AN: 2110

Alfa AF: 0.153 Hom.: 1643

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 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	4.0
DANN	Benign	0.81
PhyloP100		0.0030
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: rs3828034; hg19: chr1-66062325; COSMIC: COSV60749977;