rs35682

Positions:

• chr3-10287098-G-A
• chr3-10287098-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000335542.13(GHRL):​c.226-286C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 241,126 control chromosomes in the GnomAD database, including 42,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (26885 hom., cov: 32)
  • Exomes 𝑓: 0.58 (15579 hom.)
• Consequence: GHRL ENST00000335542.13 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.497

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-10287098-G-A is Benign according to our data. Variant chr3-10287098-G-A is described in ClinVar as [Benign]. Clinvar id is 1174428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
GHRL	NM_016362.5	c.226-286C>T		intron_variant		ENST00000335542.13	NP_057446.1
GHRLOS	NR_024145.2	n.398-847G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.226-286C>T		intron_variant		1	NM_016362.5	ENSP00000335074	P4
GHRLOS	ENST00000439539.3	n.101-316G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.586 AC: 89053 AN: 151980 Hom.: 26864 Cov.: 32

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.656

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.569

GnomAD4 exome AF: 0.578 AC: 51477 AN: 89028 Hom.: 15579 Cov.: 0 AF XY: 0.591 AC XY: 27730 AN XY: 46948

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.651

Gnomad4 ASJ exome AF: 0.572

Gnomad4 EAS exome AF: 0.984

Gnomad4 SAS exome AF: 0.791

Gnomad4 FIN exome AF: 0.555

Gnomad4 NFE exome AF: 0.506

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.586 AC: 89125 AN: 152098 Hom.: 26885 Cov.: 32 AF XY: 0.597 AC XY: 44403 AN XY: 74368

Gnomad4 AFR AF: 0.615

Gnomad4 AMR AF: 0.656

Gnomad4 ASJ AF: 0.584

Gnomad4 EAS AF: 0.976

Gnomad4 SAS AF: 0.818

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.512

Gnomad4 OTH AF: 0.569

Alfa AF: 0.529 Hom.: 20186

Bravo AF: 0.591

Asia WGS AF: 0.850 AC: 2956 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.67

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: rs35682; hg19: chr3-10328782;