rs10954173

Variant names:

• chr7-128251387-G-A
• rs10954173
• NM_000230.3:c.-28-604G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000230.3(LEP):​c.-28-604G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 152,104 control chromosomes in the GnomAD database, including 8,123 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 0.31 (8123 hom., cov: 32)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.399
• Publications: 16 publications found

Genes affected

LEP (HGNC:6553): (leptin) This gene encodes a protein that is secreted by white adipocytes into the circulation and plays a major role in the regulation of energy homeostasis. Circulating leptin binds to the leptin receptor in the brain, which activates downstream signaling pathways that inhibit feeding and promote energy expenditure. This protein also has several endocrine functions, and is involved in the regulation of immune and inflammatory responses, hematopoiesis, angiogenesis, reproduction, bone formation and wound healing. Mutations in this gene and its regulatory regions cause severe obesity and morbid obesity with hypogonadism in human patients. A mutation in this gene has also been linked to type 2 diabetes mellitus development. [provided by RefSeq, Aug 2017]

LEP Gene-Disease associations (from GenCC):

• obesity due to congenital leptin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet

ENSG00000289434 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.-28-604G>A		intron_variant	Intron 1 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.-28-604G>A		intron_variant	Intron 1 of 2		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.-28-604G>A		intron_variant	Intron 1 of 2	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1	n.168+11975C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47673 AN: 151986 Hom.: 8121 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.378

Gnomad OTH AF: 0.317

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

GnomAD4 genome AF: 0.314 AC: 47701 AN: 152104 Hom.: 8123 Cov.: 32 AF XY: 0.315 AC XY: 23391 AN XY: 74352

African (AFR) AF: 0.182 AC: 7559 AN: 41520

American (AMR) AF: 0.356 AC: 5433 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1213 AN: 3470

East Asian (EAS) AF: 0.208 AC: 1078 AN: 5188

South Asian (SAS) AF: 0.336 AC: 1621 AN: 4822

European-Finnish (FIN) AF: 0.384 AC: 4051 AN: 10544

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.378 AC: 25703 AN: 67966

Other (OTH) AF: 0.316 AC: 666 AN: 2108

Alfa AF: 0.340 Hom.: 1524

Bravo AF: 0.309

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		0.40
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: rs10954173; hg19: chr7-127891440;