rs121909359
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000163.5(GHR):c.168C>A(p.Cys56Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,368 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
GHR
NM_000163.5 stop_gained
NM_000163.5 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.57
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 Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 5-42688921-C-A is Pathogenic according to our data. Variant chr5-42688921-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 8634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-42688921-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHR | NM_000163.5 | c.168C>A | p.Cys56Ter | stop_gained | 4/10 | ENST00000230882.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHR | ENST00000230882.9 | c.168C>A | p.Cys56Ter | stop_gained | 4/10 | 1 | NM_000163.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251374Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135854
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Laron-type isolated somatotropin defect Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1991 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Dec 10, 2012 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change creates a premature translational stop signal (p.Cys56*) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849). This variant is present in population databases (rs121909359, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Laron dwarfism (PMID: 1999489). This variant is also known as C38X. ClinVar contains an entry for this variant (Variation ID: 8634). For these reasons, this variant has been classified as Pathogenic. - |
Growth hormone insensitivity syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2023 | Variant summary: GHR c.168C>A (p.Cys56X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251374 control chromosomes. c.168C>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Growth Hormone Insensitivity (examples: Woods_1997, Shapiro_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28870985, 9360502). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at