3-10290784-C-T

Position:

• chr3-10290784-C-T

Variant summary

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

The ENST00000335542.13(GHRL):​c.-98G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 989,806 control chromosomes in the GnomAD database, including 190,567 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 0.68 (35417 hom., cov: 32)
  • Exomes 𝑓: 0.61 (155150 hom.)
• Consequence: GHRL ENST00000335542.13 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.265

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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GHRL	NM_016362.5	c.-98G>A		5_prime_UTR_variant	2/6	ENST00000335542.13	NP_057446.1
GHRLOS	NR_024145.2	n.556-1284C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.-98G>A		5_prime_UTR_variant	2/6	1	NM_016362.5	ENSP00000335074	P4
GHRLOS	ENST00000439539.3	n.327-1284C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102585 AN: 151972 Hom.: 35392 Cov.: 32

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.880

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.657

GnomAD4 exome AF: 0.606 AC: 507727 AN: 837716 Hom.: 155150 Cov.: 25 AF XY: 0.606 AC XY: 234549 AN XY: 387116

Gnomad4 AFR exome AF: 0.757

Gnomad4 AMR exome AF: 0.778

Gnomad4 ASJ exome AF: 0.573

Gnomad4 EAS exome AF: 0.918

Gnomad4 SAS exome AF: 0.862

Gnomad4 FIN exome AF: 0.590

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.675 AC: 102663 AN: 152090 Hom.: 35417 Cov.: 32 AF XY: 0.682 AC XY: 50734 AN XY: 74352

Gnomad4 AFR AF: 0.753

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.906

Gnomad4 SAS AF: 0.879

Gnomad4 FIN AF: 0.607

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.654

Alfa AF: 0.638 Hom.: 8217

Bravo AF: 0.685

Asia WGS AF: 0.856 AC: 2977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.2
DANN	Benign	0.80

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: rs27647; hg19: chr3-10332468; COSMIC: COSV55055880; COSMIC: COSV55055880;