rs10954174

Variant names:

• chr7-128256483-A-G
• rs10954174
• NM_000230.3:c.*1720A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-128256483-A-G
• chr7-128256483-A-C
• chr7-128256483-A-T

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.*1720A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 152,784 control chromosomes in the GnomAD database, including 71,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71727 hom., cov: 32)
  • Exomes 𝑓: 1.0 (239 hom.)
• Consequence: LEP NM_000230.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.628
• Publications: 14 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=-0.92).
• BP6: Variant 7-128256483-A-G is Benign according to our data. Variant chr7-128256483-A-G is described in ClinVar as Benign. ClinVar VariationId is 358839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 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.*1720A>G		3_prime_UTR	Exon 3 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.*1720A>G		3_prime_UTR	Exon 3 of 3	ENSP00000312652.4	P41159
	ENSG00000289434	ENST00000785131.1		n.168+6879T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.969 AC: 147543 AN: 152186 Hom.: 71675 Cov.: 32

Gnomad AFR AF: 0.906

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 0.971

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.982

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

GnomAD4 exome AF: 0.996 AC: 478 AN: 480 Hom.: 239 Cov.: 0 AF XY: 1.00 AC XY: 294 AN XY: 294

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.667 AC: 4 AN: 6

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 408 AN: 408

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 1.00 AC: 50 AN: 50

Other (OTH) AF: 1.00 AC: 12 AN: 12

GnomAD4 genome AF: 0.969 AC: 147654 AN: 152304 Hom.: 71727 Cov.: 32 AF XY: 0.970 AC XY: 72275 AN XY: 74472

African (AFR) AF: 0.906 AC: 37624 AN: 41548

American (AMR) AF: 0.989 AC: 15128 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 3371 AN: 3470

East Asian (EAS) AF: 0.953 AC: 4928 AN: 5172

South Asian (SAS) AF: 0.982 AC: 4745 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67965 AN: 68030

Other (OTH) AF: 0.974 AC: 2061 AN: 2116

Alfa AF: 0.971 Hom.: 25363

Bravo AF: 0.967

Asia WGS AF: 0.958 AC: 3331 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.28
DANN	Benign	0.28
PhyloP100		-0.63
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: rs10954174; hg19: chr7-127896536;