chr7-128256968-G-A

Variant names:

• chr7-128256968-G-A
• rs41457646
• NM_000230.3:c.*2205G>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.*2205G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,552 control chromosomes in the GnomAD database, including 1,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1326 hom., cov: 32)
  • Exomes 𝑓: 0.11 (2 hom.)
• Consequence: LEP NM_000230.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00100
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-128256968-G-A is Benign according to our data. Variant chr7-128256968-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 358842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LEP	NM_000230.3	c.*2205G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.*2205G>A		3_prime_UTR_variant	Exon 3 of 3		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.*2205G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_000230.3	ENSP00000312652.4
ENSG00000289434	ENST00000785131.1	n.168+6394C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17295 AN: 152106 Hom.: 1325 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.0997

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.117

GnomAD4 exome AF: 0.113 AC: 37 AN: 328 Hom.: 2 Cov.: 0 AF XY: 0.115 AC XY: 22 AN XY: 192

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.500 AC: 3 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.0600 AC: 9 AN: 150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.167 AC: 23 AN: 138

Other (OTH) AF: 0.00 AC: 0 AN: 16

GnomAD4 genome AF: 0.114 AC: 17302 AN: 152224 Hom.: 1326 Cov.: 32 AF XY: 0.116 AC XY: 8609 AN XY: 74412

African (AFR) AF: 0.0298 AC: 1236 AN: 41538

American (AMR) AF: 0.156 AC: 2380 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3470

East Asian (EAS) AF: 0.122 AC: 628 AN: 5168

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4822

European-Finnish (FIN) AF: 0.0997 AC: 1057 AN: 10604

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9812 AN: 68014

Other (OTH) AF: 0.119 AC: 252 AN: 2112

Alfa AF: 0.127 Hom.: 496

Bravo AF: 0.112

Asia WGS AF: 0.192 AC: 669 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Monogenic Non-Syndromic Obesity Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Obesity due to congenital leptin deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.74
DANN	Benign	0.41
PhyloP100		0.0010
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: rs41457646; hg19: chr7-127897021;