7-128254568-C-T

Position:

• chr7-128254568-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000230.3(LEP):​c.309C>T​(p.Asn103Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,098 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: LEP NM_000230.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0800

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-128254568-C-T is Benign according to our data. Variant chr7-128254568-C-T is described in ClinVar as [Benign]. Clinvar id is 783831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-128254568-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00578 (880/152310) while in subpopulation AFR AF= 0.0197 (821/41570). AF 95% confidence interval is 0.0186. There are 8 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LEP	NM_000230.3	c.309C>T	p.Asn103Asn	synonymous_variant	3/3	ENST00000308868.5	NP_000221.1
LEP	XM_005250340.6	c.306C>T	p.Asn102Asn	synonymous_variant	3/3		XP_005250397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LEP	ENST00000308868.5	c.309C>T	p.Asn103Asn	synonymous_variant	3/3	1	NM_000230.3	ENSP00000312652.4

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152192 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00183 AC: 460 AN: 251482 Hom.: 4 AF XY: 0.00137 AC XY: 186 AN XY: 135914

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000685 AC: 1002 AN: 1461788 Hom.: 11 Cov.: 32 AF XY: 0.000608 AC XY: 442 AN XY: 727208

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00578 AC: 880 AN: 152310 Hom.: 8 Cov.: 32 AF XY: 0.00540 AC XY: 402 AN XY: 74470

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00303 Hom.: 2

Bravo AF: 0.00665

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2020	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.2
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs28954113; hg19: chr7-127894621;