rs27498

Positions:

• chr3-10292337-G-A
• chr3-10292337-G-C

Variant summary

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

The NM_016362.5(GHRL):​c.-766+505C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 158,006 control chromosomes in the GnomAD database, including 16,334 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 0.44 (15802 hom., cov: 32)
  • Exomes 𝑓: 0.41 (532 hom.)
• Consequence: GHRL NM_016362.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHRL	NM_016362.5	c.-766+505C>T		intron_variant		ENST00000335542.13
GHRLOS	NR_024145.2	n.825G>A		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHRL	ENST00000335542.13	c.-766+505C>T		intron_variant		1	NM_016362.5	P4
GHRLOS	ENST00000439539.3	n.596G>A		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66535 AN: 151900 Hom.: 15791 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.423

GnomAD4 exome AF: 0.408 AC: 2446 AN: 5988 Hom.: 532 Cov.: 0 AF XY: 0.423 AC XY: 1361 AN XY: 3220

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.583

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.384

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.438 AC: 66575 AN: 152018 Hom.: 15802 Cov.: 32 AF XY: 0.450 AC XY: 33453 AN XY: 74292

Gnomad4 AFR AF: 0.410

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.374

Gnomad4 OTH AF: 0.425

Alfa AF: 0.411 Hom.: 5497

Bravo AF: 0.444

Asia WGS AF: 0.715 AC: 2483 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	4.4
DANN	Benign	0.88

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: rs27498; hg19: chr3-10334021;