rs587778384
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_016592.5(GNAS):c.*42+13917C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,583,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000025 ( 1 hom. )
Consequence
GNAS
NM_016592.5 intron
NM_016592.5 intron
Scores
3
16
Clinical Significance
Conservation
PhyloP100: 0.0480
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 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.12494424).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNAS | NM_080425.4 | c.1538C>T | p.Ala513Val | missense_variant | 1/13 | ENST00000371100.9 | |
GNAS | NM_016592.5 | c.*42+13917C>T | intron_variant | ENST00000371075.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371100.9 | c.1538C>T | p.Ala513Val | missense_variant | 1/13 | 5 | NM_080425.4 | ||
GNAS | ENST00000371075.7 | c.*42+13917C>T | intron_variant | 1 | NM_016592.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000564 AC: 11AN: 195208Hom.: 1 AF XY: 0.0000552 AC XY: 6AN XY: 108788
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GnomAD4 exome AF: 0.0000252 AC: 36AN: 1431408Hom.: 1 Cov.: 34 AF XY: 0.0000338 AC XY: 24AN XY: 710748
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
GNAS-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 12, 2023 | The GNAS c.1538C>T variant is predicted to result in the amino acid substitution p.Ala513Val. Of note, in the more commonly reported transcript (NM_000516.5) this variant is pre-coding (c.-36924C>T). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-57429858-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L
MutationTaster
Benign
N;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Uncertain
D;D;D
Polyphen
B;.;.
Vest4
MutPred
Loss of methylation at R512 (P = 0.0867);Loss of methylation at R512 (P = 0.0867);Loss of methylation at R512 (P = 0.0867);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at