chr1-65565843-T-TCACACA

Variant names:

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

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+240insACACAC 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 0.017 (37 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-TCACACA is Benign according to our data. Variant chr1-65565843-T-TCACACA is described in ClinVar as Likely_benign. ClinVar VariationId is 1193475.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0173 (2611/150494) while in subpopulation AMR AF = 0.0275 (415/15080). AF 95% confidence interval is 0.0253. There are 37 homozygotes in GnomAd4. There are 1225 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 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+240insACACAC		intron	N/A	NP_002294.2
	LEPR	NM_001003680.3		c.40+239_40+240insACACAC		intron	N/A	NP_001003680.1	P48357-3
	LEPR	NM_001198687.2		c.40+239_40+240insACACAC		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+239insCACACA		intron	N/A	ENSP00000330393.7	P48357-1
	LEPR	ENST00000371059.7	TSL:1	c.40+238_40+239insCACACA		intron	N/A	ENSP00000360098.3	P48357-3
	LEPR	ENST00000344610.12	TSL:1	c.40+238_40+239insCACACA		intron	N/A	ENSP00000340884.8	P48357-4

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2605 AN: 150388 Hom.: 36 Cov.: 11

Gnomad AFR AF: 0.00513

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0206

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.00522

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0195

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

GnomAD4 genome AF: 0.0173 AC: 2611 AN: 150494 Hom.: 37 Cov.: 11 AF XY: 0.0167 AC XY: 1225 AN XY: 73470

African (AFR) AF: 0.00518 AC: 212 AN: 40888

American (AMR) AF: 0.0275 AC: 415 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 89 AN: 3440

East Asian (EAS) AF: 0.0207 AC: 104 AN: 5036

South Asian (SAS) AF: 0.0259 AC: 123 AN: 4750

European-Finnish (FIN) AF: 0.00522 AC: 54 AN: 10348

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.0232 AC: 1570 AN: 67682

Other (OTH) AF: 0.0198 AC: 41 AN: 2072

Alfa AF: 0.00709 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;