3-10288880-C-T

Variant names:

• chr3-10288880-C-T
• rs35680
• NM_016362.5:c.225+882G>A

Variant summary

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

The NM_016362.5(GHRL):​c.225+882G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 152,026 control chromosomes in the GnomAD database, including 28,916 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 0.61 (28916 hom., cov: 32)
• Consequence: GHRL NM_016362.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384
• Publications: 19 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 = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRL	NM_016362.5	c.225+882G>A		intron_variant	Intron 4 of 5	ENST00000335542.13	NP_057446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.225+882G>A		intron_variant	Intron 4 of 5	1	NM_016362.5	ENSP00000335074.8

Frequencies

GnomAD3 genomes AF: 0.607 AC: 92227 AN: 151908 Hom.: 28892 Cov.: 32

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.581

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

GnomAD4 genome AF: 0.607 AC: 92305 AN: 152026 Hom.: 28916 Cov.: 32 AF XY: 0.617 AC XY: 45828 AN XY: 74308

African (AFR) AF: 0.680 AC: 28196 AN: 41470

American (AMR) AF: 0.664 AC: 10161 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2014 AN: 3464

East Asian (EAS) AF: 0.975 AC: 5047 AN: 5174

South Asian (SAS) AF: 0.819 AC: 3949 AN: 4824

European-Finnish (FIN) AF: 0.553 AC: 5846 AN: 10562

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.518 AC: 35156 AN: 67926

Other (OTH) AF: 0.581 AC: 1224 AN: 2108

Alfa AF: 0.566 Hom.: 40858

Bravo AF: 0.616

Asia WGS AF: 0.858 AC: 2984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.24
DANN	Benign	0.29
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35680; hg19: chr3-10330564;