20-58909365-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000516.7(GNAS):​c.601C>A​(p.Arg201Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,402 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

GNAS
NM_000516.7 missense

Scores

16
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:3O:1

Conservation

PhyloP100: 4.12
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 12 ACMG points.

PM1
In a binding_site (size 7) in uniprot entity GNAS2_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000516.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-58909365-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAS. . Gene score misZ 2.6546 (greater than the threshold 3.09). Trascript score misZ 4.8361 (greater than threshold 3.09). GenCC has associacion of gene with ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983
PP5
Variant 20-58909365-C-A is Pathogenic according to our data. Variant chr20-58909365-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 15937.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-58909365-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GNASNM_080425.4 linkuse as main transcriptc.2530C>A p.Arg844Ser missense_variant 8/13 ENST00000371100.9
GNASNM_000516.7 linkuse as main transcriptc.601C>A p.Arg201Ser missense_variant 8/13 ENST00000371085.8
GNASNM_016592.5 linkuse as main transcriptc.*507C>A 3_prime_UTR_variant 8/13 ENST00000371075.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GNASENST00000371100.9 linkuse as main transcriptc.2530C>A p.Arg844Ser missense_variant 8/135 NM_080425.4 Q5JWF2-1
GNASENST00000371085.8 linkuse as main transcriptc.601C>A p.Arg201Ser missense_variant 8/131 NM_000516.7 P63092-1
GNASENST00000371075.7 linkuse as main transcriptc.*507C>A 3_prime_UTR_variant 8/131 NM_016592.5 O95467-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152140
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461402
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727046
show subpopulations
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:
0.0000187
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74312
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

ACTH-independent macronodular adrenal hyperplasia 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2003- -
PITUITARY TUMOR 3, GROWTH HORMONE-SECRETING, SOMATIC Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2003- -
Polyostotic fibrous dysplasia, somatic, mosaic Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2003- -
McCune-Albright syndrome Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.;.;.;D;.;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
4.2
.;.;.;.;H;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-5.3
D;D;.;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;.;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;D;.;D
Vest4
0.93
MutPred
0.89
Gain of sheet (P = 0.0827);.;.;.;.;.;.;
MVP
1.0
MPC
3.3
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs11554273; hg19: chr20-57484420; COSMIC: COSV55670675; COSMIC: COSV55670675; API