3-10290110-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016362.5(GHRL):​c.71G>C​(p.Gly24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GHRL
NM_016362.5 missense

Scores

4
12
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GHRLNM_016362.5 linkc.71G>C p.Gly24Ala missense_variant Exon 3 of 6 ENST00000335542.13 NP_057446.1 Q9UBU3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GHRLENST00000335542.13 linkc.71G>C p.Gly24Ala missense_variant Exon 3 of 6 1 NM_016362.5 ENSP00000335074.8 Q9UBU3-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000676
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000895
AC:
22
AN:
245766
Hom.:
0
AF XY:
0.0000828
AC XY:
11
AN XY:
132852
show subpopulations
Gnomad AFR exome
AF:
0.000569
Gnomad AMR exome
AF:
0.000262
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000182
Gnomad OTH exome
AF:
0.000335
GnomAD4 exome
AF:
0.0000267
AC:
39
AN:
1460852
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
726664
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.000296
AC XY:
22
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.000676
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.000261
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 24, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.71G>C (p.G24A) alteration is located in exon 2 (coding exon 1) of the GHRL gene. This alteration results from a G to C substitution at nucleotide position 71, causing the glycine (G) at amino acid position 24 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.;D;D;.
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.92
.;.;D;D;.;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.60
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.17
D
MutationAssessor
Uncertain
2.9
M;M;M;M;M;M;.
PROVEAN
Pathogenic
-5.4
D;D;D;D;D;D;D
REVEL
Uncertain
0.55
Sift
Pathogenic
0.0
D;D;D;D;D;D;.
Sift4G
Uncertain
0.021
D;D;D;D;D;D;.
Polyphen
1.0
D;D;.;D;D;D;.
Vest4
0.76
MVP
0.79
MPC
0.054
ClinPred
0.62
D
GERP RS
4.9
Varity_R
0.87
gMVP
0.41

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149396238; hg19: chr3-10331794; API