3-10291242-C-G

Variant names:

• chr3-10291242-C-G
• rs26311
• NM_016362.5:c.-556G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001302821.2(GHRL):​c.-307G>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 985,314 control chromosomes in the GnomAD database, including 8,607 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2358 hom., cov: 33)
  • Exomes 𝑓: 0.12 (6249 hom.)
• Consequence: GHRL NM_001302821.2 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.640

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHRL	NM_016362.5	c.-556G>C		5_prime_UTR_variant	Exon 2 of 6	ENST00000335542.13	NP_057446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.-556G>C		5_prime_UTR_variant	Exon 2 of 6	1	NM_016362.5	ENSP00000335074.8

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24408 AN: 152082 Hom.: 2350 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.118 AC: 98244 AN: 833114 Hom.: 6249 Cov.: 32 AF XY: 0.118 AC XY: 45319 AN XY: 384738

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.415

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.161 AC: 24438 AN: 152200 Hom.: 2358 Cov.: 33 AF XY: 0.162 AC XY: 12049 AN XY: 74420

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.408

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.146

Alfa AF: 0.133 Hom.: 200

Bravo AF: 0.161

Asia WGS AF: 0.238 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs26311; hg19: chr3-10332926;