7-128254252-G-A

Variant names:

• chr7-128254252-G-A
• rs3828942
• NM_000230.3:c.145-152G>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.145-152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 909,420 control chromosomes in the GnomAD database, including 93,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12628 hom., cov: 32)
  • Exomes 𝑓: 0.45 (80917 hom.)
• Consequence: LEP NM_000230.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.54

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]

ENSG00000289434 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-128254252-G-A is Benign according to our data. Variant chr7-128254252-G-A is described in ClinVar as [Benign]. Clinvar id is 1247016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.145-152G>A		intron_variant	Intron 2 of 2	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.145-155G>A		intron_variant	Intron 2 of 2		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.145-152G>A		intron_variant	Intron 2 of 2	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1	n.168+9110C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58183 AN: 151892 Hom.: 12620 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.734

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.462

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.450 AC: 340882 AN: 757412 Hom.: 80917 AF XY: 0.455 AC XY: 181354 AN XY: 398366

African (AFR) AF: 0.183 AC: 3679 AN: 20140

American (AMR) AF: 0.411 AC: 17124 AN: 41692

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 7948 AN: 19210

East Asian (EAS) AF: 0.761 AC: 27715 AN: 36430

South Asian (SAS) AF: 0.519 AC: 34210 AN: 65854

European-Finnish (FIN) AF: 0.465 AC: 17142 AN: 36838

Middle Eastern (MID) AF: 0.448 AC: 1254 AN: 2798

European-Non Finnish (NFE) AF: 0.433 AC: 215385 AN: 497088

Other (OTH) AF: 0.440 AC: 16425 AN: 37362

GnomAD4 genome AF: 0.383 AC: 58212 AN: 152008 Hom.: 12628 Cov.: 32 AF XY: 0.391 AC XY: 29015 AN XY: 74292

African (AFR) AF: 0.187 AC: 7753 AN: 41462

American (AMR) AF: 0.439 AC: 6703 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1406 AN: 3470

East Asian (EAS) AF: 0.735 AC: 3787 AN: 5154

South Asian (SAS) AF: 0.522 AC: 2513 AN: 4812

European-Finnish (FIN) AF: 0.462 AC: 4878 AN: 10566

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.439 AC: 29834 AN: 67950

Other (OTH) AF: 0.389 AC: 821 AN: 2112

Alfa AF: 0.418 Hom.: 6154

Bravo AF: 0.369

Asia WGS AF: 0.623 AC: 2163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0050
DANN	Benign	0.54
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs3828942; hg19: chr7-127894305; COSMIC: COSV58240657;