1-65565843-T-TCACACA

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 11. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.40+239_40+240insACACAC		intron_variant		ENST00000349533.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.40+239_40+240insACACAC		intron_variant		1	NM_002303.6	P4

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

Gnomad4 AFR AF: 0.00518

Gnomad4 AMR AF: 0.0275

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.0207

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.00522

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.00709 Hom.: 248

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs67805092; hg19: chr1-66031526;