rs9679845

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000461152.6(GNAS):​c.343G>A​(p.Glu115Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 151,448 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.042 ( 167 hom., cov: 32)

Consequence

GNAS
ENST00000461152.6 missense

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.41
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 -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.042 (6355/151448) while in subpopulation AMR AF= 0.0521 (792/15216). AF 95% confidence interval is 0.049. There are 167 homozygotes in gnomad4. There are 3063 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 167 SM,Mitochondrial gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GNASNM_016592.5 linkc.*43-5389G>A intron_variant Intron 1 of 12 ENST00000371075.7 NP_057676.1 O95467-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GNASENST00000461152.6 linkc.343G>A p.Glu115Lys missense_variant Exon 1 of 3 5 ENSP00000499274.1 A0A590UJ46
GNASENST00000371075.7 linkc.*43-5389G>A intron_variant Intron 1 of 12 1 NM_016592.5 ENSP00000360115.3 O95467-1
GNASENST00000676826.2 linkc.2069-5389G>A intron_variant Intron 1 of 12 ENSP00000504675.2 A0A7I2V5R6
GNASENST00000371102.8 linkc.2069-5389G>A intron_variant Intron 1 of 11 5 ENSP00000360143.4 Q5JWF2-2
GNASENST00000470512.6 linkc.-39+870G>A intron_variant Intron 1 of 12 5 ENSP00000499552.2 A0A590UJQ9
GNASENST00000480232.6 linkc.-39+674G>A intron_variant Intron 2 of 13 5 ENSP00000499545.2 A0A590UJQ9
GNASENST00000663479.2 linkc.-38-5389G>A intron_variant Intron 1 of 12 ENSP00000499353.2 A0A590UJQ9
GNASENST00000462499.6 linkc.-38-5389G>A intron_variant Intron 1 of 11 2 ENSP00000499758.2 A0A590UK28
GNASENST00000467227.6 linkc.-38-5389G>A intron_variant Intron 2 of 12 3 ENSP00000499681.2 A0A590UK28
GNASENST00000478585.6 linkc.-39+870G>A intron_variant Intron 1 of 11 2 ENSP00000499762.2 A0A590UK28
GNASENST00000481039.6 linkc.-39+1315G>A intron_variant Intron 1 of 11 5 ENSP00000499767.2 A0A590UK28
GNASENST00000485673.6 linkc.-39+674G>A intron_variant Intron 1 of 11 5 ENSP00000499334.2 A0A590UK28
GNASENST00000488546.6 linkc.-39+1405G>A intron_variant Intron 1 of 11 5 ENSP00000499332.2 A0A590UK28
GNASENST00000453292.7 linkc.*43-5389G>A intron_variant Intron 1 of 11 5 ENSP00000392000.2 O95467-1A2A2S1

Frequencies

GnomAD3 genomes
AF:
0.0419
AC:
6348
AN:
151336
Hom.:
166
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0384
Gnomad AMI
AF:
0.0384
Gnomad AMR
AF:
0.0521
Gnomad ASJ
AF:
0.0572
Gnomad EAS
AF:
0.00564
Gnomad SAS
AF:
0.0133
Gnomad FIN
AF:
0.0261
Gnomad MID
AF:
0.0860
Gnomad NFE
AF:
0.0477
Gnomad OTH
AF:
0.0538
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.0420
AC:
6355
AN:
151448
Hom.:
167
Cov.:
32
AF XY:
0.0414
AC XY:
3063
AN XY:
74036
show subpopulations
Gnomad4 AFR
AF:
0.0384
Gnomad4 AMR
AF:
0.0521
Gnomad4 ASJ
AF:
0.0572
Gnomad4 EAS
AF:
0.00565
Gnomad4 SAS
AF:
0.0140
Gnomad4 FIN
AF:
0.0261
Gnomad4 NFE
AF:
0.0478
Gnomad4 OTH
AF:
0.0538
Alfa
AF:
0.0391
Hom.:
89
Bravo
AF:
0.0447
Asia WGS
AF:
0.0130
AC:
45
AN:
3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
CADD
Benign
16
DANN
Benign
0.88

Splicing

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: rs9679845; hg19: chr20-57465278; API