rs121909361
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5
The NM_000163.5(GHR):c.184G>A(p.Glu62Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,458 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 (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
GHR
NM_000163.5 missense
NM_000163.5 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 6.40
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 5 ACMG points.
PM1
?
In a disulfide_bond (size 10) in uniprot entity GHR_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000163.5
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.87
PP5
?
Variant 5-42688937-G-A is Pathogenic according to our data. Variant chr5-42688937-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8636.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-42688937-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHR | NM_000163.5 | c.184G>A | p.Glu62Lys | missense_variant | 4/10 | ENST00000230882.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHR | ENST00000230882.9 | c.184G>A | p.Glu62Lys | missense_variant | 4/10 | 1 | NM_000163.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251356Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461314Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727006
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74310
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Short stature due to partial GHR deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 26, 1995 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;D;.;D;D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;M;M;M;M;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;.;.;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;.;.;.;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D
Polyphen
D;D;.;D;D;D;D;.;.
Vest4
MVP
MPC
ClinPred
D
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