3-10291680-C-G

Variant names:

• chr3-10291680-C-G
• rs3755777
• NM_016362.5:c.-765-229G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016362.5(GHRL):​c.-765-229G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,188 control chromosomes in the GnomAD database, including 5,561 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5561 hom., cov: 33)
• Consequence: GHRL NM_016362.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 16 publications found

Genes affected

GHRL (HGNC:18129): (ghrelin and obestatin prepropeptide) This gene encodes the ghrelin-obestatin preproprotein that is cleaved to yield two peptides, ghrelin and obestatin. Ghrelin is a powerful appetite stimulant and plays an important role in energy homeostasis. Its secretion is initiated when the stomach is empty, whereupon it binds to the growth hormone secretagogue receptor in the hypothalamus which results in the secretion of growth hormone (somatotropin). Ghrelin is thought to regulate multiple activities, including hunger, reward perception via the mesolimbic pathway, gastric acid secretion, gastrointestinal motility, and pancreatic glucose-stimulated insulin secretion. It was initially proposed that obestatin plays an opposing role to ghrelin by promoting satiety and thus decreasing food intake, but this action is still debated. Recent reports suggest multiple metabolic roles for obestatin, including regulating adipocyte function and glucose metabolism. Alternative splicing results in multiple transcript variants. In addition, antisense transcripts for this gene have been identified and may potentially regulate ghrelin-obestatin preproprotein expression. [provided by RefSeq, Nov 2014]

GHRLOS (HGNC:33885): (ghrelin opposite strand/antisense RNA) This gene is an antisense gene of the ghrelin/obestatin prepropeptide gene. Alternatively spliced transcript variants have been identified and they may function as non-coding regulatory RNAs. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRL	NM_016362.5	c.-765-229G>C		intron_variant	Intron 1 of 5	ENST00000335542.13	NP_057446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.-765-229G>C		intron_variant	Intron 1 of 5	1	NM_016362.5	ENSP00000335074.8

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35348 AN: 152070 Hom.: 5562 Cov.: 33

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.462

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.230

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.232 AC: 35348 AN: 152188 Hom.: 5561 Cov.: 33 AF XY: 0.245 AC XY: 18223 AN XY: 74396

African (AFR) AF: 0.0618 AC: 2569 AN: 41552

American (AMR) AF: 0.397 AC: 6075 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 707 AN: 3470

East Asian (EAS) AF: 0.494 AC: 2556 AN: 5178

South Asian (SAS) AF: 0.460 AC: 2218 AN: 4824

European-Finnish (FIN) AF: 0.341 AC: 3605 AN: 10568

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16765 AN: 67982

Other (OTH) AF: 0.231 AC: 488 AN: 2112

Alfa AF: 0.237 Hom.: 670

Bravo AF: 0.229

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.090
DANN	Benign	0.46
PhyloP100		-1.4
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: rs3755777; hg19: chr3-10333364;