1-65480223-T-C

Position:

• chr1-65480223-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002303.6(LEPR):​c.-21+54845T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 151,500 control chromosomes in the GnomAD database, including 22,970 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22970 hom., cov: 31)
• Consequence: LEPR NM_002303.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEPR	NM_002303.6	c.-21+54845T>C		intron_variant		ENST00000349533.11
LEPR	NM_001003679.3	c.-21+54845T>C		intron_variant
LEPR	NM_001003680.3	c.-21+54845T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEPR	ENST00000349533.11	c.-21+54845T>C		intron_variant		1	NM_002303.6	P4
LEPR	ENST00000371059.7	c.-21+54845T>C		intron_variant		1
LEPR	ENST00000371060.7	c.-21+54845T>C		intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.541 AC: 81881 AN: 151384 Hom.: 22965 Cov.: 31

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.567

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

GnomAD4 genome AF: 0.541 AC: 81924 AN: 151500 Hom.: 22970 Cov.: 31 AF XY: 0.534 AC XY: 39503 AN XY: 74000

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.585

Gnomad4 ASJ AF: 0.667

Gnomad4 EAS AF: 0.0796

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.565

Alfa AF: 0.438 Hom.: 1171

Bravo AF: 0.544

Asia WGS AF: 0.322 AC: 1124 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs7554485; hg19: chr1-65945906;