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

Genomes: not found (cov: 28)

Consequence

GNAS
NM_000516.7 initiator_codon

Scores

4
3
9

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.80
Variant links:
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 20 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 29 pathogenic variants. Next in-frame start position is after 60 codons. Genomic position: 58895650. Lost 0.150 part of the original CDS.
PS1
Another start lost variant in NM_000516.7 (GNAS) was described as [Likely_pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 20-58891727-A-T is Pathogenic according to our data. Variant chr20-58891727-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 419339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNASNM_000516.7 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 13 ENST00000371085.8 NP_000507.1 P63092-1O95467A0A0S2Z3H8
GNASNM_016592.5 linkc.*43-3885A>T intron_variant Intron 1 of 12 ENST00000371075.7 NP_057676.1 O95467-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNASENST00000371085.8 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 13 1 NM_000516.7 ENSP00000360126.3 P63092-1
GNASENST00000354359.12 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 13 1 ENSP00000346328.7 P63092-4
GNASENST00000371095.7 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 12 1 ENSP00000360136.3 P63092-2
GNASENST00000371075.7 linkc.*43-3885A>T intron_variant Intron 1 of 12 1 NM_016592.5 ENSP00000360115.3 O95467-1
GNASENST00000676826.2 linkc.2069-3885A>T intron_variant Intron 1 of 12 ENSP00000504675.2 A0A7I2V5R6
GNASENST00000371102.8 linkc.2069-3885A>T intron_variant Intron 1 of 11 5 ENSP00000360143.4 Q5JWF2-2
GNASENST00000470512.6 linkc.-39+2374A>T intron_variant Intron 1 of 12 5 ENSP00000499552.2 A0A590UJQ9
GNASENST00000480232.6 linkc.-39+2178A>T intron_variant Intron 2 of 13 5 ENSP00000499545.2 A0A590UJQ9
GNASENST00000663479.2 linkc.-38-3885A>T intron_variant Intron 1 of 12 ENSP00000499353.2 A0A590UJQ9
GNASENST00000462499.6 linkc.-38-3885A>T intron_variant Intron 1 of 11 2 ENSP00000499758.2 A0A590UK28
GNASENST00000467227.6 linkc.-38-3885A>T intron_variant Intron 2 of 12 3 ENSP00000499681.2 A0A590UK28
GNASENST00000478585.6 linkc.-39+2374A>T intron_variant Intron 1 of 11 2 ENSP00000499762.2 A0A590UK28
GNASENST00000481039.6 linkc.-39+2819A>T intron_variant Intron 1 of 11 5 ENSP00000499767.2 A0A590UK28
GNASENST00000485673.6 linkc.-39+2178A>T intron_variant Intron 1 of 11 5 ENSP00000499334.2 A0A590UK28
GNASENST00000488546.6 linkc.-39+2909A>T intron_variant Intron 1 of 11 5 ENSP00000499332.2 A0A590UK28
GNASENST00000461152.6 linkc.*51+938A>T intron_variant Intron 1 of 2 5 ENSP00000499274.1 A0A590UJ46
GNASENST00000453292.7 linkc.*43-3885A>T intron_variant Intron 1 of 11 5 ENSP00000392000.2 O95467-1A2A2S1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Feb 26, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 26, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jul 21, 2015
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Benign
23
DANN
Benign
0.88
DEOGEN2
Benign
0.34
.;T;.;.;T;T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Uncertain
0.46
D
PROVEAN
Benign
-1.4
N;N;N;N;N;N
REVEL
Uncertain
0.62
Sift
Benign
0.031
D;D;D;D;T;D
Sift4G
Benign
0.088
T;T;T;T;D;D
Polyphen
0.38, 0.33
.;B;.;B;.;.
Vest4
0.79
MutPred
0.97
Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);
MVP
1.0
ClinPred
0.74
D
GERP RS
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137854530; hg19: chr20-57466782; API