chr5-42699978-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_ModeratePP5_Moderate
The NM_000163.5(GHR):āc.594A>Gā(p.Glu198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,449,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
GHR
NM_000163.5 synonymous
NM_000163.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.647
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 4 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 5-42699978-A-G is Pathogenic according to our data. Variant chr5-42699978-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 8635.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHR | NM_000163.5 | c.594A>G | p.Glu198= | synonymous_variant | 6/10 | ENST00000230882.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHR | ENST00000230882.9 | c.594A>G | p.Glu198= | synonymous_variant | 6/10 | 1 | NM_000163.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250634Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135458
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GnomAD4 exome AF: 0.00000414 AC: 6AN: 1449718Hom.: 0 Cov.: 27 AF XY: 0.00000415 AC XY: 3AN XY: 722040
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Laron-type isolated somatotropin defect Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2002 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in the activation of a cryptic splice site in exon 6 (PMID: 1284474). ClinVar contains an entry for this variant (Variation ID: 8635). This variant is also known as E180splice. This variant has been observed in individuals with Laron syndrome (PMID: 1284474, 2233903, 8504296, 24664892). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909360, gnomAD 0.006%). This sequence change affects codon 198 of the GHR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GHR protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
DS_DL_spliceai
Position offset: 24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at