rs137854530
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000516.7(GNAS):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000996 in 1,004,328 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 (★★).
Frequency
Genomes: not found (cov: 28)
Exomes 𝑓: 0.0000010 ( 0 hom. )
Consequence
GNAS
NM_000516.7 start_lost
NM_000516.7 start_lost
Scores
6
3
6
Clinical Significance
Conservation
PhyloP100: 6.80
Genes affected
GNAS (HGNC:4392): (GNAS complex locus) This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-58891727-A-G is Pathogenic according to our data. Variant chr20-58891727-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58891727-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNAS | NM_000516.7 | c.1A>G | p.Met1? | start_lost | 1/13 | ENST00000371085.8 | |
GNAS | NM_016592.5 | c.*43-3885A>G | intron_variant | ENST00000371075.7 | |||
GNAS | NM_080425.4 | c.2069-3885A>G | intron_variant | ENST00000371100.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371085.8 | c.1A>G | p.Met1? | start_lost | 1/13 | 1 | NM_000516.7 | ||
GNAS | ENST00000371075.7 | c.*43-3885A>G | intron_variant | 1 | NM_016592.5 | ||||
GNAS | ENST00000371100.9 | c.2069-3885A>G | intron_variant | 5 | NM_080425.4 |
Frequencies
GnomAD3 genomes ? Cov.: 28
GnomAD3 genomes
?
Cov.:
28
GnomAD4 exome AF: 9.96e-7 AC: 1AN: 1004328Hom.: 0 Cov.: 32 AF XY: 0.00000206 AC XY: 1AN XY: 486476
GnomAD4 exome
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AC:
1
AN:
1004328
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
486476
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 28
GnomAD4 genome
?
Cov.:
28
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | 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. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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, 21713996). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15927). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2021 | Initiation codon variants (Met1?) in GNAS likely lead to the use of an alternate initiation codon and the loss of the first 59 residues (Patten JL et al., 1990; Puzhko S et al., 2011); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 2109828, 27535533, 31546270) - |
Pseudohypoparathyroidism Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 17, 1990 | - - |
Cushing syndrome;C0033806:Pseudohypoparathyroidism;C0033835:Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C4540135:Pituitary adenoma 3, multiple types Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A
PROVEAN
Benign
N;N;N;N;D;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
0.99, 0.99
.;D;.;D;.;.
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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