rs8386

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.08
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 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
GNASNM_000516.7 linkuse as main transcriptc.1113C>T p.Asn371Asn synonymous_variant 13/13 ENST00000371085.8 NP_000507.1 P63092-1O95467A0A0S2Z3H8
GNASNM_016592.5 linkuse as main transcriptc.*1019C>T 3_prime_UTR_variant 13/13 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.1113C>T p.Asn371Asn synonymous_variant 13/131 NM_000516.7 ENSP00000360126.3 P63092-1
GNASENST00000676826.2 linkuse as main transcriptc.3045C>T p.Asn1015Asn synonymous_variant 13/13 ENSP00000504675.2 A0A7I2V5R6
GNASENST00000371102.8 linkuse as main transcriptc.3000C>T p.Asn1000Asn synonymous_variant 12/125 ENSP00000360143.4 Q5JWF2-2
GNASENST00000354359.12 linkuse as main transcriptc.1116C>T p.Asn372Asn synonymous_variant 13/131 ENSP00000346328.7 P63092-4
GNASENST00000371095.7 linkuse as main transcriptc.1071C>T p.Asn357Asn synonymous_variant 12/121 ENSP00000360136.3 P63092-2
GNASENST00000470512.6 linkuse as main transcriptc.939C>T p.Asn313Asn synonymous_variant 13/135 ENSP00000499552.2 A0A590UJQ9
GNASENST00000480232.6 linkuse as main transcriptc.939C>T p.Asn313Asn synonymous_variant 14/145 ENSP00000499545.2 A0A590UJQ9
GNASENST00000663479.2 linkuse as main transcriptc.939C>T p.Asn313Asn synonymous_variant 13/13 ENSP00000499353.2 A0A590UJQ9
GNASENST00000462499.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 12/122 ENSP00000499758.2 A0A590UK28
GNASENST00000467227.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 13/133 ENSP00000499681.2 A0A590UK28
GNASENST00000478585.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 12/122 ENSP00000499762.2 A0A590UK28
GNASENST00000481039.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 12/125 ENSP00000499767.2 A0A590UK28
GNASENST00000485673.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 12/125 ENSP00000499334.2 A0A590UK28
GNASENST00000488546.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 12/125 ENSP00000499332.2 A0A590UK28
GNASENST00000492907.6 linkuse as main transcriptc.894C>T p.Asn298Asn synonymous_variant 12/123 ENSP00000499443.2 A0A590UK28
GNASENST00000371075.7 linkuse as main transcriptc.*1019C>T 3_prime_UTR_variant 13/131 NM_016592.5 ENSP00000360115.3 O95467-1
GNASENST00000453292.7 linkuse as main transcriptc.*974C>T 3_prime_UTR_variant 12/125 ENSP00000392000.2 O95467-1A2A2S1

Frequencies

GnomAD3 genomes
AF:
0.0568
AC:
8645
AN:
152148
Hom.:
633
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.172
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0253
Gnomad ASJ
AF:
0.0228
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.0108
Gnomad FIN
AF:
0.00386
Gnomad MID
AF:
0.0443
Gnomad NFE
AF:
0.0131
Gnomad OTH
AF:
0.0359
GnomAD3 exomes
AF:
0.0218
AC:
5490
AN:
251460
Hom.:
280
AF XY:
0.0189
AC XY:
2571
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.173
Gnomad AMR exome
AF:
0.0140
Gnomad ASJ exome
AF:
0.0199
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0108
Gnomad FIN exome
AF:
0.00323
Gnomad NFE exome
AF:
0.0129
Gnomad OTH exome
AF:
0.0215
GnomAD4 exome
AF:
0.0162
AC:
23698
AN:
1461600
Hom.:
708
Cov.:
32
AF XY:
0.0157
AC XY:
11394
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.180
Gnomad4 AMR exome
AF:
0.0154
Gnomad4 ASJ exome
AF:
0.0212
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0109
Gnomad4 FIN exome
AF:
0.00300
Gnomad4 NFE exome
AF:
0.0124
Gnomad4 OTH exome
AF:
0.0213
GnomAD4 genome
AF:
0.0568
AC:
8655
AN:
152266
Hom.:
633
Cov.:
32
AF XY:
0.0552
AC XY:
4113
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.171
Gnomad4 AMR
AF:
0.0252
Gnomad4 ASJ
AF:
0.0228
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0110
Gnomad4 FIN
AF:
0.00386
Gnomad4 NFE
AF:
0.0131
Gnomad4 OTH
AF:
0.0355
Alfa
AF:
0.0263
Hom.:
244
Bravo
AF:
0.0628
Asia WGS
AF:
0.0130
AC:
44
AN:
3478
EpiCase
AF:
0.0164
EpiControl
AF:
0.0157

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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 31, 2018- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not specified Benign:2
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.31
CADD
Benign
13
DANN
Benign
0.95
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: rs8386; hg19: chr20-57485812; COSMIC: COSV55686986; COSMIC: COSV55686986; API