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

Genomes: not found (cov: 28)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GNAS
NM_000516.7 start_lost

Scores

8
3
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 3.26
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 13 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 20-58891728-T-C is Pathogenic according to our data. Variant chr20-58891728-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 499177.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNASNM_000516.7 linkc.2T>C p.Met1? start_lost Exon 1 of 13 ENST00000371085.8 NP_000507.1 P63092-1O95467A0A0S2Z3H8
GNASNM_016592.5 linkc.*43-3884T>C 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.2T>C p.Met1? start_lost Exon 1 of 13 1 NM_000516.7 ENSP00000360126.3 P63092-1
GNASENST00000354359.12 linkc.2T>C p.Met1? start_lost Exon 1 of 13 1 ENSP00000346328.7 P63092-4
GNASENST00000371095.7 linkc.2T>C p.Met1? start_lost Exon 1 of 12 1 ENSP00000360136.3 P63092-2
GNASENST00000371075.7 linkc.*43-3884T>C intron_variant Intron 1 of 12 1 NM_016592.5 ENSP00000360115.3 O95467-1
GNASENST00000676826.2 linkc.2069-3884T>C intron_variant Intron 1 of 12 ENSP00000504675.2 A0A7I2V5R6
GNASENST00000371102.8 linkc.2069-3884T>C intron_variant Intron 1 of 11 5 ENSP00000360143.4 Q5JWF2-2
GNASENST00000470512.6 linkc.-39+2375T>C intron_variant Intron 1 of 12 5 ENSP00000499552.2 A0A590UJQ9
GNASENST00000480232.6 linkc.-39+2179T>C intron_variant Intron 2 of 13 5 ENSP00000499545.2 A0A590UJQ9
GNASENST00000663479.2 linkc.-38-3884T>C intron_variant Intron 1 of 12 ENSP00000499353.2 A0A590UJQ9
GNASENST00000462499.6 linkc.-38-3884T>C intron_variant Intron 1 of 11 2 ENSP00000499758.2 A0A590UK28
GNASENST00000467227.6 linkc.-38-3884T>C intron_variant Intron 2 of 12 3 ENSP00000499681.2 A0A590UK28
GNASENST00000478585.6 linkc.-39+2375T>C intron_variant Intron 1 of 11 2 ENSP00000499762.2 A0A590UK28
GNASENST00000481039.6 linkc.-39+2820T>C intron_variant Intron 1 of 11 5 ENSP00000499767.2 A0A590UK28
GNASENST00000485673.6 linkc.-39+2179T>C intron_variant Intron 1 of 11 5 ENSP00000499334.2 A0A590UK28
GNASENST00000488546.6 linkc.-39+2910T>C intron_variant Intron 1 of 11 5 ENSP00000499332.2 A0A590UK28
GNASENST00000461152.6 linkc.*51+939T>C intron_variant Intron 1 of 2 5 ENSP00000499274.1 A0A590UJ46
GNASENST00000453292.7 linkc.*43-3884T>C intron_variant Intron 1 of 11 5 ENSP00000392000.2 O95467-1A2A2S1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1005396
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
487100
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Jun 09, 2024
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 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. -

Jan 13, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Uncertain:1
Mar 23, 2022
Institute of Human Genetics, University Hospital Muenster
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG categories: PM2,PP5 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.27
CADD
Uncertain
24
DANN
Benign
0.95
DEOGEN2
Uncertain
0.54
.;D;.;.;T;T
Eigen
Benign
0.18
Eigen_PC
Benign
0.047
FATHMM_MKL
Benign
0.28
N
LIST_S2
Uncertain
0.90
D;D;D;D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D
REVEL
Pathogenic
0.79
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
1.0
.;D;.;D;.;.
Vest4
0.57
MutPred
0.98
Gain of phosphorylation at M1 (P = 0.0771);Gain of phosphorylation at M1 (P = 0.0771);Gain of phosphorylation at M1 (P = 0.0771);Gain of phosphorylation at M1 (P = 0.0771);Gain of phosphorylation at M1 (P = 0.0771);Gain of phosphorylation at M1 (P = 0.0771);
MVP
0.91
ClinPred
0.90
D
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3

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: rs1555883949; hg19: chr20-57466783; API