rs121909367
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The ENST00000230882.9(GHR):āc.512T>Cā(p.Ile171Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,453,294 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 Likely pathogenic (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000034 ( 0 hom. )
Consequence
GHR
ENST00000230882.9 missense
ENST00000230882.9 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 7.42
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 10 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000230882.9
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 5-42699896-T-C is Pathogenic according to our data. Variant chr5-42699896-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8654.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-42699896-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GHR | NM_000163.5 | c.512T>C | p.Ile171Thr | missense_variant | 6/10 | ENST00000230882.9 | NP_000154.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GHR | ENST00000230882.9 | c.512T>C | p.Ile171Thr | missense_variant | 6/10 | 1 | NM_000163.5 | ENSP00000230882 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1453294Hom.: 0 Cov.: 26 AF XY: 0.00000138 AC XY: 1AN XY: 723618
GnomAD4 exome
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5
AN:
1453294
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Cov.:
26
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1
AN XY:
723618
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely 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 | Dec 01, 1998 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2023 | Variant reported in trans with an exon 9 deletion in a patient with growth hormone insensitivity, whose mother was heterozygous for the variant and 25-50% height in the published literature (Wojcik et al., 1998; Gastier et al., 2000); Published functional study demonstrates a damaging effect; variant causes abnormal trafficking (Wojcik et al., 1998); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11013443, 9851797) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;D;D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;.;D;.;.;D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.;M;M;M;M;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
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
MutPred
Loss of stability (P = 0.06);Loss of stability (P = 0.06);.;Loss of stability (P = 0.06);Loss of stability (P = 0.06);Loss of stability (P = 0.06);Loss of stability (P = 0.06);.;Loss of stability (P = 0.06);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at