rs143814221
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_000163.5(GHR):āc.718T>Cā(p.Tyr240His) variant causes a missense change. The variant allele was found at a frequency of 0.00024 in 1,613,336 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00023 ( 0 hom., cov: 33)
Exomes š: 0.00024 ( 1 hom. )
Consequence
GHR
NM_000163.5 missense
NM_000163.5 missense
Scores
7
8
3
Clinical Significance
Conservation
PhyloP100: 4.63
Genes affected
GHR (HGNC:4263): (growth hormone receptor) This gene encodes a member of the type I cytokine receptor family, which is a transmembrane receptor for growth hormone. Binding of growth hormone to the receptor leads to receptor dimerization and the activation of an intra- and intercellular signal transduction pathway leading to growth. Mutations in this gene have been associated with Laron syndrome, also known as the growth hormone insensitivity syndrome (GHIS), a disorder characterized by short stature. In humans and rabbits, but not rodents, growth hormone binding protein (GHBP) is generated by proteolytic cleavage of the extracellular ligand-binding domain from the mature growth hormone receptor protein. Multiple alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jun 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a strand (size 3) in uniprot entity GHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000163.5
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHR | NM_000163.5 | c.718T>C | p.Tyr240His | missense_variant | 7/10 | ENST00000230882.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHR | ENST00000230882.9 | c.718T>C | p.Tyr240His | missense_variant | 7/10 | 1 | NM_000163.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152142Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000274 AC: 69AN: 251388Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135862
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GnomAD4 exome AF: 0.000241 AC: 352AN: 1461076Hom.: 1 Cov.: 30 AF XY: 0.000270 AC XY: 196AN XY: 726910
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GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20AN XY: 74462
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Laron-type isolated somatotropin defect Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | May 04, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 18, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 12, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 240 of the GHR protein (p.Tyr240His). This variant is present in population databases (rs143814221, gnomAD 0.05%). This missense change has been observed in individual(s) with growth hormone insensitivity (PMID: 10984309). This variant is also known as p.Tyr222His. ClinVar contains an entry for this variant (Variation ID: 198398). 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 expected to disrupt GHR protein function. 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. - |
Seizure;C0349588:Short stature;C0544755:Genu varum;C1849075:Relative macrocephaly;C1849937:Disproportionate short-limb short stature;C1866239:Mesomelic/rhizomelic limb shortening;C4025790:Specific learning disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Laron-type isolated somatotropin defect;C1858656:Short stature due to partial GHR deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Sep 01, 2023 | - - |
Short stature due to partial GHR deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 01, 2020 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;D;D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;M;M;M;M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;.;.;.;.;N;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;.;.;D;.
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;D;D;D;D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at