Genetic Variant GHRL:p.Leu72Val (chr3-10289771-CAG-AAC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_016362.5(GHRL):c.214_216delCTGinsGTT (p.Leu72Val) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L72M: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 5062)

Frequency

Genomes: not found (cov: 31)

Consequence

GHRL
NM_016362.5 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.01

Publications

0 publications found

Variant links:

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]

GHRL links:

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]

GHRLOS links:

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new If you want to explore the variant's impact on the transcript NM_016362.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: unknown) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_016362.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
GHRL NM_016362.5	MANE Select	c.214_216delCTGinsGTT p.Leu72Val	missense	N/A	Prot: NP_057446.1 UniProt: Q9UBU3-1
GHRL NM_001302821.2		c.214_216delCTGinsGTT p.Leu72Val	missense	N/A	Prot: NP_001289750.1 UniProt: Q9UBU3-1
GHRL NM_001302822.2		c.214_216delCTGinsGTT p.Leu72Val	missense	N/A	Prot: NP_001289751.1 UniProt: Q9UBU3-1

GHRL NM_016362.5

MANE Select

HGVSc / HGVSpc.214_216delCTGinsGTTp.Leu72Val

Exon rankN/A

missense

Prot: NP_057446.1UniProt: Q9UBU3-1

GHRL NM_001302821.2

HGVSc / HGVSpc.214_216delCTGinsGTTp.Leu72Val

Exon rankN/A

missense

Prot: NP_001289750.1UniProt: Q9UBU3-1

GHRL NM_001302822.2

HGVSc / HGVSpc.214_216delCTGinsGTTp.Leu72Val

Exon rankN/A

missense

Prot: NP_001289751.1UniProt: Q9UBU3-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
GHRL ENST00000335542.13	TSL:1MANE Select	c.214_216delCTGinsGTT p.Leu72Val	missense	N/A	Prot: ENSP00000335074.8 UniProt: Q9UBU3-1
GHRL ENST00000429122.1	TSL:1	c.214_216delCTGinsGTT p.Leu72Val	missense	N/A	Prot: ENSP00000414819.1 UniProt: Q9UBU3-1
GHRL ENST00000457360.5	TSL:1	c.214_216delCTGinsGTT p.Leu72Val	missense	N/A	Prot: ENSP00000391406.1 UniProt: Q9UBU3-1

GHRL ENST00000335542.13

TSL:1MANE Select

HGVSc / HGVSpc.214_216delCTGinsGTTp.Leu72Val

Exon rankN/A

missense

Prot: ENSP00000335074.8UniProt: Q9UBU3-1

GHRL ENST00000429122.1

TSL:1

HGVSc / HGVSpc.214_216delCTGinsGTTp.Leu72Val

Exon rankN/A

missense

Prot: ENSP00000414819.1UniProt: Q9UBU3-1

GHRL ENST00000457360.5

TSL:1

HGVSc / HGVSpc.214_216delCTGinsGTTp.Leu72Val

Exon rankN/A

missense

Prot: ENSP00000391406.1UniProt: Q9UBU3-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence