1-65565843-T-TCA

Variant names:

• chr1-65565843-T-TCA
• rs67805092
• NM_002303.6:c.40+239_40+240insAC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_002303.6(LEPR):​c.40+239_40+240insAC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.016 (33 hom., cov: 11)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.79
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-65565843-T-TCA is Benign according to our data. Variant chr1-65565843-T-TCA is described in ClinVar as Likely_benign. ClinVar VariationId is 1187101.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.016 (2401/150368) while in subpopulation AFR AF = 0.03 (1227/40866). AF 95% confidence interval is 0.0286. There are 33 homozygotes in GnomAd4. There are 1192 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002303.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	NM_002303.6	MANE Select	c.40+239_40+240insAC		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.40+239_40+240insAC		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.40+239_40+240insAC		intron	N/A	NP_001185616.1	P48357-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEPR	ENST00000349533.11	TSL:1 MANE Select	c.40+238_40+239insCA		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.40+238_40+239insCA		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.40+238_40+239insCA		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2396 AN: 150266 Hom.: 33 Cov.: 11

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00119

Gnomad SAS AF: 0.00357

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.0176

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

GnomAD4 genome AF: 0.0160 AC: 2401 AN: 150368 Hom.: 33 Cov.: 11 AF XY: 0.0162 AC XY: 1192 AN XY: 73396

African (AFR) AF: 0.0300 AC: 1227 AN: 40866

American (AMR) AF: 0.0112 AC: 169 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3444

East Asian (EAS) AF: 0.00119 AC: 6 AN: 5028

South Asian (SAS) AF: 0.00358 AC: 17 AN: 4752

European-Finnish (FIN) AF: 0.0241 AC: 248 AN: 10306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0103 AC: 694 AN: 67630

Other (OTH) AF: 0.0174 AC: 36 AN: 2068

Alfa AF: 0.00308 Hom.: 248

ClinVar

ClinVar submissions

Significance: Likely 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
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs67805092; hg19: chr1-66031526;