rs2167270

Variant names:

• chr7-128241296-G-A
• rs2167270
• NM_000230.3:c.-39G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000230.3(LEP):​c.-39G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 154,068 control chromosomes in the GnomAD database, including 10,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10565 hom., cov: 33)
  • Exomes 𝑓: 0.34 (124 hom.)
• Consequence: LEP NM_000230.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.12
• Publications: 194 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000289434 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-128241296-G-A is Benign according to our data. Variant chr7-128241296-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 358814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000230.3. 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
	LEP	NM_000230.3	MANE Select	c.-39G>A		5_prime_UTR	Exon 1 of 3	NP_000221.1	P41159

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LEP	ENST00000308868.5	TSL:1 MANE Select	c.-39G>A		5_prime_UTR	Exon 1 of 3	ENSP00000312652.4	P41159
	LEP	ENST00000965599.1		c.-39G>A		5_prime_UTR	Exon 1 of 3	ENSP00000635658.1
	ENSG00000289434	ENST00000785131.1		n.169-19756C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56252 AN: 151972 Hom.: 10557 Cov.: 33

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.366

GnomAD4 exome AF: 0.335 AC: 663 AN: 1978 Hom.: 124 Cov.: 0 AF XY: 0.337 AC XY: 361 AN XY: 1072

African (AFR) AF: 0.594 AC: 19 AN: 32

American (AMR) AF: 0.417 AC: 10 AN: 24

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12 AN: 26

East Asian (EAS) AF: 0.141 AC: 27 AN: 192

South Asian (SAS) AF: 0.500 AC: 6 AN: 12

European-Finnish (FIN) AF: 0.354 AC: 204 AN: 576

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.344 AC: 355 AN: 1032

Other (OTH) AF: 0.350 AC: 28 AN: 80

GnomAD4 genome AF: 0.370 AC: 56309 AN: 152090 Hom.: 10565 Cov.: 33 AF XY: 0.366 AC XY: 27225 AN XY: 74348

African (AFR) AF: 0.409 AC: 16960 AN: 41510

American (AMR) AF: 0.378 AC: 5776 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1213 AN: 3468

East Asian (EAS) AF: 0.198 AC: 1023 AN: 5156

South Asian (SAS) AF: 0.295 AC: 1423 AN: 4830

European-Finnish (FIN) AF: 0.342 AC: 3619 AN: 10590

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25141 AN: 67946

Other (OTH) AF: 0.364 AC: 767 AN: 2108

Alfa AF: 0.375 Hom.: 15000

Bravo AF: 0.380

Asia WGS AF: 0.238 AC: 830 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Monogenic Non-Syndromic Obesity (1)
-	-	1	Obesity due to congenital leptin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		2.1
PromoterAI		-0.16	Neutral
Mutation Taster		=300/0	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: rs2167270; hg19: chr7-127881349; COSMIC: COSV58241049;