20-58903579-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_000516.7(GNAS):​c.306G>T​(p.Ala102Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,820 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 (★). Synonymous variant affecting the same amino acid position (i.e. A102A) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GNAS
NM_000516.7 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.179
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
Variant 20-58903579-G-T is Benign according to our data. Variant chr20-58903579-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 800031.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
Synonymous conserved (PhyloP=-0.179 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GNASNM_000516.7 linkuse as main transcriptc.306G>T p.Ala102Ala synonymous_variant 4/13 ENST00000371085.8 NP_000507.1 P63092-1O95467A0A0S2Z3H8
GNASNM_016592.5 linkuse as main transcriptc.*212G>T 3_prime_UTR_variant 4/13 ENST00000371075.7 NP_057676.1 O95467-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNASENST00000371085.8 linkuse as main transcriptc.306G>T p.Ala102Ala synonymous_variant 4/131 NM_000516.7 ENSP00000360126.3 P63092-1
GNASENST00000676826.2 linkuse as main transcriptc.2238G>T p.Ala746Ala synonymous_variant 4/13 ENSP00000504675.2 A0A7I2V5R6
GNASENST00000371102.8 linkuse as main transcriptc.2193G>T p.Ala731Ala synonymous_variant 3/125 ENSP00000360143.4 Q5JWF2-2
GNASENST00000354359.12 linkuse as main transcriptc.309G>T p.Ala103Ala synonymous_variant 4/131 ENSP00000346328.7 P63092-4
GNASENST00000371095.7 linkuse as main transcriptc.264G>T p.Ala88Ala synonymous_variant 3/121 ENSP00000360136.3 P63092-2
GNASENST00000470512.6 linkuse as main transcriptc.132G>T p.Ala44Ala synonymous_variant 4/135 ENSP00000499552.2 A0A590UJQ9
GNASENST00000480232.6 linkuse as main transcriptc.132G>T p.Ala44Ala synonymous_variant 5/145 ENSP00000499545.2 A0A590UJQ9
GNASENST00000663479.2 linkuse as main transcriptc.132G>T p.Ala44Ala synonymous_variant 4/13 ENSP00000499353.2 A0A590UJQ9
GNASENST00000462499.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 3/122 ENSP00000499758.2 A0A590UK28
GNASENST00000467227.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 4/133 ENSP00000499681.2 A0A590UK28
GNASENST00000478585.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 3/122 ENSP00000499762.2 A0A590UK28
GNASENST00000481039.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 3/125 ENSP00000499767.2 A0A590UK28
GNASENST00000485673.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 3/125 ENSP00000499334.2 A0A590UK28
GNASENST00000488546.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 3/125 ENSP00000499332.2 A0A590UK28
GNASENST00000492907.6 linkuse as main transcriptc.87G>T p.Ala29Ala synonymous_variant 3/123 ENSP00000499443.2 A0A590UK28
GNASENST00000371075.7 linkuse as main transcriptc.*212G>T 3_prime_UTR_variant 4/131 NM_016592.5 ENSP00000360115.3 O95467-1
GNASENST00000461152.6 linkuse as main transcriptc.*176G>T 3_prime_UTR_variant 3/35 ENSP00000499274.1 A0A590UJ46
GNASENST00000453292.7 linkuse as main transcriptc.*167G>T 3_prime_UTR_variant 3/125 ENSP00000392000.2 O95467-1A2A2S1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251484
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461820
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000378
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 03, 2023- -
GNAS-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 13, 2021This 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
CADD
Benign
5.3
DANN
Benign
0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs117849691; hg19: chr20-57478634; COSMIC: COSV104548875; COSMIC: COSV104548875; API