3-172447803-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_198407.2(GHSR):c.611C>A(p.Ala204Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A204A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

GHSR
NM_198407.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

GHSR (HGNC:4267): (growth hormone secretagogue receptor) This gene encodes a member of the G-protein coupled receptor family. The encoded protein may play a role in energy homeostasis and regulation of body weight. Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the Ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for Ghrelin; however, it may function to attenuate activity of isoform 1a. Mutations in this gene are associated with autosomal idiopathic short stature.[provided by RefSeq, Apr 2010]

GHSR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 3-172447803-G-T is Pathogenic according to our data. Variant chr3-172447803-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7632.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr3-172447803-G-T is described in Lovd as [Pathogenic]. Variant chr3-172447803-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GHSR	NM_198407.2 linkuse as main transcript	c.611C>A	p.Ala204Glu	missense_variant	1/2	ENST00000241256.3
GHSR	NM_004122.2 linkuse as main transcript	c.611C>A	p.Ala204Glu	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GHSR	ENST00000241256.3 linkuse as main transcript	c.611C>A	p.Ala204Glu	missense_variant	1/2	1	NM_198407.2	P1	Q92847-1
GHSR	ENST00000427970.1 linkuse as main transcript	c.611C>A	p.Ala204Glu	missense_variant	1/1				Q92847-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249640

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461694

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000405

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 22, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 204 of the GHSR protein (p.Ala204Glu). This variant is present in population databases (rs121917883, gnomAD 0.005%). This missense change has been observed in individual(s) with GFSR-related conditions (PMID: 14715843, 16511605, 25557026). ClinVar contains an entry for this variant (Variation ID: 7632). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GHSR protein function. Experimental studies have shown that this missense change affects GHSR function (PMID: 16511605, 17596538, 17717076, 21084395). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Short stature due to growth hormone secretagogue receptor deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.15

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

0.99

D;D

Vest4

0.95

MutPred

0.84

Gain of disorder (P = 0.0284);Gain of disorder (P = 0.0284);

MVP

0.85

MPC

2.1

ClinPred

0.76

GERP RS

5.5

Varity_R

0.97

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.61

Position offset: -1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over