20-58891727-A-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000516.7(GNAS):c.1A>T(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000516.7 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371085.8 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 13 | 1 | NM_000516.7 | ENSP00000360126.3 | ||
GNAS | ENST00000354359.12 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 13 | 1 | ENSP00000346328.7 | |||
GNAS | ENST00000371095.7 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 12 | 1 | ENSP00000360136.3 | |||
GNAS | ENST00000371075.7 | c.*43-3885A>T | intron_variant | Intron 1 of 12 | 1 | NM_016592.5 | ENSP00000360115.3 | |||
GNAS | ENST00000676826.2 | c.2069-3885A>T | intron_variant | Intron 1 of 12 | ENSP00000504675.2 | |||||
GNAS | ENST00000371102.8 | c.2069-3885A>T | intron_variant | Intron 1 of 11 | 5 | ENSP00000360143.4 | ||||
GNAS | ENST00000470512.6 | c.-39+2374A>T | intron_variant | Intron 1 of 12 | 5 | ENSP00000499552.2 | ||||
GNAS | ENST00000480232.6 | c.-39+2178A>T | intron_variant | Intron 2 of 13 | 5 | ENSP00000499545.2 | ||||
GNAS | ENST00000663479.2 | c.-38-3885A>T | intron_variant | Intron 1 of 12 | ENSP00000499353.2 | |||||
GNAS | ENST00000462499.6 | c.-38-3885A>T | intron_variant | Intron 1 of 11 | 2 | ENSP00000499758.2 | ||||
GNAS | ENST00000467227.6 | c.-38-3885A>T | intron_variant | Intron 2 of 12 | 3 | ENSP00000499681.2 | ||||
GNAS | ENST00000478585.6 | c.-39+2374A>T | intron_variant | Intron 1 of 11 | 2 | ENSP00000499762.2 | ||||
GNAS | ENST00000481039.6 | c.-39+2819A>T | intron_variant | Intron 1 of 11 | 5 | ENSP00000499767.2 | ||||
GNAS | ENST00000485673.6 | c.-39+2178A>T | intron_variant | Intron 1 of 11 | 5 | ENSP00000499334.2 | ||||
GNAS | ENST00000488546.6 | c.-39+2909A>T | intron_variant | Intron 1 of 11 | 5 | ENSP00000499332.2 | ||||
GNAS | ENST00000461152.6 | c.*51+938A>T | intron_variant | Intron 1 of 2 | 5 | ENSP00000499274.1 | ||||
GNAS | ENST00000453292.7 | c.*43-3885A>T | intron_variant | Intron 1 of 11 | 5 | ENSP00000392000.2 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 28
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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This sequence change affects the initiator methionine of the GNAS mRNA. The next in-frame methionine is located at codon 60. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with GNAS-related conditions (PMID: 21713996). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 419339). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GNAS function (PMID: 21713996). For these reasons, this variant has been classified as Pathogenic. -
The c.1 A>T variant in the GNAS gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.1 A>T substitution alters the initiatorMethionine codon, and the resultant protein would be described as p.Met1? using a question mark tosignify that it is not known if the loss of Met1 means that all protein translation is completely prevented orif an abnormal protein is produced using an alternate Methionine. The c.1 A>T variant was not observedin approximately 6400 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Missense variantsin involving the same residue (M1V, M1R, M1I) have been reported in the Human Gene MutationDatabase in association with Albright Hereditary Osteodystrophy (Stenson et al., 2014), supporting thefunctional importance of this region of the protein. Additionally, functional characterization of a similarsubstitution (M1I) at the initiation codon resulted in a protein that is truncated by 59 amino acids at the Nterminus (Puzhko et al., 2011). We interpret c.1 A>T as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at