rs587778389
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate
The NM_016592.5(GNAS):c.*42+13514G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,566,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
GNAS
NM_016592.5 intron
NM_016592.5 intron
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: -0.157
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 Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.105068415).
BP6
?
Variant 20-58854400-G-C is Benign according to our data. Variant chr20-58854400-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 134494.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GNAS | NM_080425.4 | c.1135G>C | p.Gly379Arg | missense_variant | 1/13 | ENST00000371100.9 | |
GNAS | NM_016592.5 | c.*42+13514G>C | intron_variant | ENST00000371075.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371100.9 | c.1135G>C | p.Gly379Arg | missense_variant | 1/13 | 5 | NM_080425.4 | ||
GNAS | ENST00000371075.7 | c.*42+13514G>C | intron_variant | 1 | NM_016592.5 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152218Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000819 AC: 14AN: 170898Hom.: 0 AF XY: 0.000108 AC XY: 10AN XY: 92466
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GnomAD4 exome AF: 0.000241 AC: 341AN: 1413868Hom.: 0 Cov.: 34 AF XY: 0.000237 AC XY: 166AN XY: 699180
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74360
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
GNAS-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 01, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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
Benign
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
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
Uncertain
D;D;D
Sift4G
Uncertain
D;T;D
Polyphen
B;.;.
Vest4
MutPred
Gain of methylation at G379 (P = 0.0301);Gain of methylation at G379 (P = 0.0301);Gain of methylation at G379 (P = 0.0301);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at