3-10291242-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302821.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRL	NM_016362.5	MANE Select	c.-556G>C		5_prime_UTR	Exon 2 of 6	NP_057446.1	Q9UBU3-1
	GHRL	NM_001302821.2		c.-307G>C		splice_region	Exon 2 of 7	NP_001289750.1	Q9UBU3-1
	GHRL	NM_001302821.2		c.-307G>C		5_prime_UTR	Exon 2 of 7	NP_001289750.1	Q9UBU3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GHRL	ENST00000335542.13	TSL:1 MANE Select	c.-556G>C		5_prime_UTR	Exon 2 of 6	ENSP00000335074.8	Q9UBU3-1
	GHRL	ENST00000287656.11	TSL:1	c.-556G>C		5_prime_UTR	Exon 2 of 6	ENSP00000287656.7	Q9UBU3-2
	GHRL	ENST00000429122.1	TSL:1	c.-226-330G>C		intron	N/A	ENSP00000414819.1	Q9UBU3-1

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

African (AFR) AF: 0.225 AC: 3552 AN: 15782

American (AMR) AF: 0.118 AC: 116 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 988 AN: 5150

East Asian (EAS) AF: 0.415 AC: 1506 AN: 3632

South Asian (SAS) AF: 0.116 AC: 1917 AN: 16460

European-Finnish (FIN) AF: 0.113 AC: 32 AN: 282

Middle Eastern (MID) AF: 0.154 AC: 250 AN: 1620

European-Non Finnish (NFE) AF: 0.113 AC: 86008 AN: 761908

Other (OTH) AF: 0.142 AC: 3875 AN: 27296

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

African (AFR) AF: 0.221 AC: 9184 AN: 41512

American (AMR) AF: 0.127 AC: 1939 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3470

East Asian (EAS) AF: 0.408 AC: 2105 AN: 5164

South Asian (SAS) AF: 0.132 AC: 636 AN: 4826

European-Finnish (FIN) AF: 0.151 AC: 1599 AN: 10610

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7915 AN: 68004

Other (OTH) AF: 0.146 AC: 309 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.34
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs26311; hg19: chr3-10332926;