rs26312

Positions:

• chr3-10291174-G-A

Variant summary

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

The NM_016362.5(GHRL):​c.-488C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 985,506 control chromosomes in the GnomAD database, including 9,391 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 0.16 (2344 hom., cov: 33)
  • Exomes 𝑓: 0.13 (7047 hom.)
• Consequence: GHRL NM_016362.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47

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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRL	NM_016362.5	c.-488C>T		5_prime_UTR_variant	2/6	ENST00000335542.13	NP_057446.1
GHRLOS	NR_024145.2	n.556-894G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.-488C>T		5_prime_UTR_variant	2/6	1	NM_016362.5	ENSP00000335074	P4
GHRLOS	ENST00000439539.3	n.327-894G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24560 AN: 152126 Hom.: 2338 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.125 AC: 104551 AN: 833262 Hom.: 7047 Cov.: 32 AF XY: 0.125 AC XY: 48271 AN XY: 384844

Gnomad4 AFR exome AF: 0.216

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.154

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.161 AC: 24586 AN: 152244 Hom.: 2344 Cov.: 33 AF XY: 0.163 AC XY: 12167 AN XY: 74440

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.146

Alfa AF: 0.137 Hom.: 204

Bravo AF: 0.160

Asia WGS AF: 0.261 AC: 908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.17
DANN	Benign	0.57

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: rs26312; hg19: chr3-10332858;