NM_000163.5:c.497G>A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000163.5(GHR):c.497G>A(p.Gly166Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,608,710 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 Uncertain significance (★★).
Frequency
Consequence
NM_000163.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250948Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135582
GnomAD4 exome AF: 0.00000481 AC: 7AN: 1456552Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1AN XY: 724992
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: GHR c.497G>A (p.Gly166Glu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250948 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.497G>A has been reported in the literature in individuals affected with short stature with non-growth-hormone deficiency and Congenital hypogonadotropic hypogonadism (Song_2006 and Chen_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Growth Hormone Insensitivity. 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: 32502767, 32171629, 17274879, 36123965). ClinVar contains an entry for this variant (Variation ID: 225374). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Short stature due to partial GHR deficiency Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at