rs35683

Variant names:

• chr3-10286566-A-C
• rs35683
• NM_016362.5:c.334+138T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-10286566-A-C
• chr3-10286566-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016362.5(GHRL):​c.334+138T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 594,828 control chromosomes in the GnomAD database, including 112,236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27934 hom., cov: 33)
  • Exomes 𝑓: 0.60 (84302 hom.)
• Consequence: GHRL NM_016362.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.794
• Publications: 42 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-10286566-A-C is Benign according to our data. Variant chr3-10286566-A-C is described in ClinVar as Benign. ClinVar VariationId is 1265406.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 rank	MANE	Protein	UniProt
GHRL	NM_016362.5	c.334+138T>G		intron_variant	Intron 5 of 5	ENST00000335542.13	NP_057446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHRL	ENST00000335542.13	c.334+138T>G		intron_variant	Intron 5 of 5	1	NM_016362.5	ENSP00000335074.8

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90883 AN: 151986 Hom.: 27912 Cov.: 33

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.823

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.578

GnomAD4 exome AF: 0.600 AC: 265837 AN: 442724 Hom.: 84302 AF XY: 0.610 AC XY: 142269 AN XY: 233128

African (AFR) AF: 0.633 AC: 7776 AN: 12288

American (AMR) AF: 0.694 AC: 13383 AN: 19288

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 7676 AN: 13290

East Asian (EAS) AF: 0.985 AC: 29409 AN: 29850

South Asian (SAS) AF: 0.811 AC: 34888 AN: 43028

European-Finnish (FIN) AF: 0.562 AC: 21341 AN: 37986

Middle Eastern (MID) AF: 0.556 AC: 1931 AN: 3472

European-Non Finnish (NFE) AF: 0.521 AC: 134723 AN: 258382

Other (OTH) AF: 0.585 AC: 14710 AN: 25140

GnomAD4 genome AF: 0.598 AC: 90957 AN: 152104 Hom.: 27934 Cov.: 33 AF XY: 0.608 AC XY: 45208 AN XY: 74360

African (AFR) AF: 0.636 AC: 26370 AN: 41484

American (AMR) AF: 0.662 AC: 10124 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2036 AN: 3472

East Asian (EAS) AF: 0.976 AC: 5048 AN: 5174

South Asian (SAS) AF: 0.823 AC: 3967 AN: 4822

European-Finnish (FIN) AF: 0.557 AC: 5897 AN: 10580

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35578 AN: 67966

Other (OTH) AF: 0.578 AC: 1223 AN: 2116

Alfa AF: 0.541 Hom.: 29909

Bravo AF: 0.605

Asia WGS AF: 0.856 AC: 2976 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.67
DANN	Benign	0.65
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35683; hg19: chr3-10328250;