chr3-172447803-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_198407.2(GHSR):c.611C>A(p.Ala204Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,860 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A204A) has been classified as Likely benign.
Frequency
Consequence
NM_198407.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHSR | NM_198407.2 | c.611C>A | p.Ala204Glu | missense_variant | 1/2 | ENST00000241256.3 | |
GHSR | NM_004122.2 | c.611C>A | p.Ala204Glu | missense_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHSR | ENST00000241256.3 | c.611C>A | p.Ala204Glu | missense_variant | 1/2 | 1 | NM_198407.2 | P1 | |
GHSR | ENST00000427970.1 | c.611C>A | p.Ala204Glu | missense_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249640Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135208
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461694Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19AN XY: 727144
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152166Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 204 of the GHSR protein (p.Ala204Glu). This variant is present in population databases (rs121917883, gnomAD 0.005%). This missense change has been observed in individual(s) with GFSR-related conditions (PMID: 14715843, 16511605, 25557026). ClinVar contains an entry for this variant (Variation ID: 7632). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GHSR protein function. Experimental studies have shown that this missense change affects GHSR function (PMID: 16511605, 17596538, 17717076, 21084395). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Short stature due to growth hormone secretagogue receptor deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2006 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at