20-58840147-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_016592.5(GNAS):​c.41G>T​(p.Arg14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,611,396 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 Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

GNAS
NM_016592.5 missense

Scores

4
7
7

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.10
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GNASNM_016592.5 linkuse as main transcriptc.41G>T p.Arg14Leu missense_variant 1/13 ENST00000371075.7 NP_057676.1 O95467-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNASENST00000371075.7 linkuse as main transcriptc.41G>T p.Arg14Leu missense_variant 1/131 NM_016592.5 ENSP00000360115.3 O95467-1
GNASENST00000453292.7 linkuse as main transcriptc.41G>T p.Arg14Leu missense_variant 1/125 ENSP00000392000.2 O95467-1A2A2S1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152080
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00000822
AC:
12
AN:
1459316
Hom.:
0
Cov.:
36
AF XY:
0.00000964
AC XY:
7
AN XY:
726058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152080
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74270
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
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
Bravo
AF:
0.0000416
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

GNAS-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 13, 2024The GNAS c.41G>T variant is predicted to result in the amino acid substitution p.Arg14Leu. Of note, in the more commonly reported transcript (NM_000516.5) this variant is pre-coding (c.-51580G>T). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;D;D
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.73
.;.;T
M_CAP
Benign
0.0037
T
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
1.1
L;L;L
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
-1.6
N;N;N
REVEL
Uncertain
0.55
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.70
MutPred
0.76
Loss of disorder (P = 0.0197);Loss of disorder (P = 0.0197);Loss of disorder (P = 0.0197);
MVP
0.24
ClinPred
0.91
D
GERP RS
3.8

Splicing

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: rs548132075; hg19: chr20-57415202; API