20-58891728-T-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PS1_ModeratePM2PP5
The NM_000516.7(GNAS):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000516.7 start_lost
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371085.8 | c.2T>C | p.Met1? | start_lost | Exon 1 of 13 | 1 | NM_000516.7 | ENSP00000360126.3 | ||
GNAS | ENST00000354359.12 | c.2T>C | p.Met1? | start_lost | Exon 1 of 13 | 1 | ENSP00000346328.7 | |||
GNAS | ENST00000371095.7 | c.2T>C | p.Met1? | start_lost | Exon 1 of 12 | 1 | ENSP00000360136.3 | |||
GNAS | ENST00000371075.7 | c.*43-3884T>C | intron_variant | Intron 1 of 12 | 1 | NM_016592.5 | ENSP00000360115.3 | |||
GNAS | ENST00000676826.2 | c.2069-3884T>C | intron_variant | Intron 1 of 12 | ENSP00000504675.2 | |||||
GNAS | ENST00000371102.8 | c.2069-3884T>C | intron_variant | Intron 1 of 11 | 5 | ENSP00000360143.4 | ||||
GNAS | ENST00000470512.6 | c.-39+2375T>C | intron_variant | Intron 1 of 12 | 5 | ENSP00000499552.2 | ||||
GNAS | ENST00000480232.6 | c.-39+2179T>C | intron_variant | Intron 2 of 13 | 5 | ENSP00000499545.2 | ||||
GNAS | ENST00000663479.2 | c.-38-3884T>C | intron_variant | Intron 1 of 12 | ENSP00000499353.2 | |||||
GNAS | ENST00000462499.6 | c.-38-3884T>C | intron_variant | Intron 1 of 11 | 2 | ENSP00000499758.2 | ||||
GNAS | ENST00000467227.6 | c.-38-3884T>C | intron_variant | Intron 2 of 12 | 3 | ENSP00000499681.2 | ||||
GNAS | ENST00000478585.6 | c.-39+2375T>C | intron_variant | Intron 1 of 11 | 2 | ENSP00000499762.2 | ||||
GNAS | ENST00000481039.6 | c.-39+2820T>C | intron_variant | Intron 1 of 11 | 5 | ENSP00000499767.2 | ||||
GNAS | ENST00000485673.6 | c.-39+2179T>C | intron_variant | Intron 1 of 11 | 5 | ENSP00000499334.2 | ||||
GNAS | ENST00000488546.6 | c.-39+2910T>C | intron_variant | Intron 1 of 11 | 5 | ENSP00000499332.2 | ||||
GNAS | ENST00000461152.6 | c.*51+939T>C | intron_variant | Intron 1 of 2 | 5 | ENSP00000499274.1 | ||||
GNAS | ENST00000453292.7 | c.*43-3884T>C | intron_variant | Intron 1 of 11 | 5 | ENSP00000392000.2 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1005396Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 487100
GnomAD4 genome Cov.: 28
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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 Albright’s hereditary osteodystrophy (PMID: 2109828, 17164301, 21713996). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 499177). Algorithms developed to predict the effect of variants on gene product 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. -
- -
See cases Uncertain:1
ACMG categories: PM2,PP5 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at