20-58840147-G-T
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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
NM_016592.5 missense
Scores
4
7
7
Clinical Significance
Conservation
PhyloP100: 4.10
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 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 |
---|---|---|---|---|---|---|---|---|
GNAS | NM_016592.5 | c.41G>T | p.Arg14Leu | missense_variant | 1/13 | ENST00000371075.7 | NP_057676.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371075.7 | c.41G>T | p.Arg14Leu | missense_variant | 1/13 | 1 | NM_016592.5 | ENSP00000360115.3 | ||
GNAS | ENST00000453292.7 | c.41G>T | p.Arg14Leu | missense_variant | 1/12 | 5 | ENSP00000392000.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152080Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459316Hom.: 0 Cov.: 36 AF XY: 0.00000964 AC XY: 7AN XY: 726058
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74270
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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 provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 13, 2024 | The 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
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;.;T
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;D;D
Vest4
MutPred
Loss of disorder (P = 0.0197);Loss of disorder (P = 0.0197);Loss of disorder (P = 0.0197);
MVP
ClinPred
D
GERP RS
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at