rs8386
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1
The NM_000516.7(GNAS):c.1113C>T(p.Asn371Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,866 control chromosomes in the GnomAD database, including 1,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.057 ( 633 hom., cov: 32)
Exomes 𝑓: 0.016 ( 708 hom. )
Consequence
GNAS
NM_000516.7 synonymous
NM_000516.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 3.08
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 Benign. Variant got -19 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31).
BP6
Variant 20-58910757-C-T is Benign according to our data. Variant chr20-58910757-C-T is described in ClinVar as [Benign]. Clinvar id is 1166174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58910757-C-T is described in Lovd as [Benign]. Variant chr20-58910757-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=3.08 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNAS | NM_000516.7 | c.1113C>T | p.Asn371Asn | synonymous_variant | 13/13 | ENST00000371085.8 | NP_000507.1 | |
GNAS | NM_016592.5 | c.*1019C>T | 3_prime_UTR_variant | 13/13 | ENST00000371075.7 | NP_057676.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNAS | ENST00000371085.8 | c.1113C>T | p.Asn371Asn | synonymous_variant | 13/13 | 1 | NM_000516.7 | ENSP00000360126.3 | ||
GNAS | ENST00000676826.2 | c.3045C>T | p.Asn1015Asn | synonymous_variant | 13/13 | ENSP00000504675.2 | ||||
GNAS | ENST00000371102.8 | c.3000C>T | p.Asn1000Asn | synonymous_variant | 12/12 | 5 | ENSP00000360143.4 | |||
GNAS | ENST00000354359.12 | c.1116C>T | p.Asn372Asn | synonymous_variant | 13/13 | 1 | ENSP00000346328.7 | |||
GNAS | ENST00000371095.7 | c.1071C>T | p.Asn357Asn | synonymous_variant | 12/12 | 1 | ENSP00000360136.3 | |||
GNAS | ENST00000470512.6 | c.939C>T | p.Asn313Asn | synonymous_variant | 13/13 | 5 | ENSP00000499552.2 | |||
GNAS | ENST00000480232.6 | c.939C>T | p.Asn313Asn | synonymous_variant | 14/14 | 5 | ENSP00000499545.2 | |||
GNAS | ENST00000663479.2 | c.939C>T | p.Asn313Asn | synonymous_variant | 13/13 | ENSP00000499353.2 | ||||
GNAS | ENST00000462499.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 12/12 | 2 | ENSP00000499758.2 | |||
GNAS | ENST00000467227.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 13/13 | 3 | ENSP00000499681.2 | |||
GNAS | ENST00000478585.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 12/12 | 2 | ENSP00000499762.2 | |||
GNAS | ENST00000481039.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 12/12 | 5 | ENSP00000499767.2 | |||
GNAS | ENST00000485673.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 12/12 | 5 | ENSP00000499334.2 | |||
GNAS | ENST00000488546.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 12/12 | 5 | ENSP00000499332.2 | |||
GNAS | ENST00000492907.6 | c.894C>T | p.Asn298Asn | synonymous_variant | 12/12 | 3 | ENSP00000499443.2 | |||
GNAS | ENST00000371075.7 | c.*1019C>T | 3_prime_UTR_variant | 13/13 | 1 | NM_016592.5 | ENSP00000360115.3 | |||
GNAS | ENST00000453292.7 | c.*974C>T | 3_prime_UTR_variant | 12/12 | 5 | ENSP00000392000.2 |
Frequencies
GnomAD3 genomes AF: 0.0568 AC: 8645AN: 152148Hom.: 633 Cov.: 32
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GnomAD3 exomes AF: 0.0218 AC: 5490AN: 251460Hom.: 280 AF XY: 0.0189 AC XY: 2571AN XY: 135910
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GnomAD4 exome AF: 0.0162 AC: 23698AN: 1461600Hom.: 708 Cov.: 32 AF XY: 0.0157 AC XY: 11394AN XY: 727122
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GnomAD4 genome AF: 0.0568 AC: 8655AN: 152266Hom.: 633 Cov.: 32 AF XY: 0.0552 AC XY: 4113AN XY: 74456
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 31, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at