rs1938485

Variant names:

• chr1-65616401-A-G
• rs1938485
• NM_002303.6:c.2212+177A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000349533.11(LEPR):​c.2212+177A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 151,998 control chromosomes in the GnomAD database, including 17,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (17181 hom., cov: 32)
• Consequence: LEPR ENST00000349533.11 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0460
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-65616401-A-G is Benign according to our data. Variant chr1-65616401-A-G is described in ClinVar as Benign. ClinVar VariationId is 1254375.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000349533.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.2212+177A>G		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.2212+177A>G		intron	N/A	NP_001003680.1
	LEPR	NM_001198687.2		c.2212+177A>G		intron	N/A	NP_001185616.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.2212+177A>G		intron	N/A	ENSP00000330393.7
	LEPR	ENST00000371059.7	TSL:1	c.2212+177A>G		intron	N/A	ENSP00000360098.3
	LEPR	ENST00000344610.12	TSL:1	c.2212+177A>G		intron	N/A	ENSP00000340884.8

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70248 AN: 151878 Hom.: 17143 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.435

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.463 AC: 70341 AN: 151998 Hom.: 17181 Cov.: 32 AF XY: 0.470 AC XY: 34913 AN XY: 74274

African (AFR) AF: 0.549 AC: 22773 AN: 41462

American (AMR) AF: 0.485 AC: 7392 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3468

East Asian (EAS) AF: 0.869 AC: 4496 AN: 5172

South Asian (SAS) AF: 0.462 AC: 2232 AN: 4828

European-Finnish (FIN) AF: 0.490 AC: 5170 AN: 10548

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

European-Non Finnish (NFE) AF: 0.377 AC: 25630 AN: 67944

Other (OTH) AF: 0.442 AC: 935 AN: 2116

Alfa AF: 0.449 Hom.: 4866

Bravo AF: 0.466

Asia WGS AF: 0.628 AC: 2178 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.73
PhyloP100		-0.046
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: rs1938485; hg19: chr1-66082084; COSMIC: COSV60750146; COSMIC: COSV60750146;