rs6123837

Positions:

• chr20-58890516-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The ENST00000461152.6(GNAS):​c.636G>A​(p.Ser212Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 152,126 control chromosomes in the GnomAD database, including 9,353 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (9329 hom., cov: 32)
  • Exomes 𝑓: 0.43 (24 hom.)
• Consequence: GNAS ENST00000461152.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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]

GNAS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*43-5096G>A		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000461152.6	c.636G>A	p.Ser212Ser	synonymous_variant	1/3	5		ENSP00000499274.1
GNAS	ENST00000371075.7	c.*43-5096G>A		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-5096G>A		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-5096G>A		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+1163G>A		intron_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+967G>A		intron_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-5096G>A		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-5096G>A		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-5096G>A		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+1163G>A		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+1608G>A		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+967G>A		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+1698G>A		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000453292.7	c.*43-5096G>A		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47218 AN: 151782 Hom.: 9334 Cov.: 32

Gnomad AFR AF: 0.0826

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.339

GnomAD4 exome AF: 0.432 AC: 102 AN: 236 Hom.: 24 AF XY: 0.443 AC XY: 78 AN XY: 176

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 1.00

Gnomad4 ASJ exome AF: 0.333

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.412

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.311 AC: 47205 AN: 151890 Hom.: 9329 Cov.: 32 AF XY: 0.321 AC XY: 23785 AN XY: 74204

Gnomad4 AFR AF: 0.0823

Gnomad4 AMR AF: 0.429

Gnomad4 ASJ AF: 0.432

Gnomad4 EAS AF: 0.672

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.359

Gnomad4 OTH AF: 0.337

Alfa AF: 0.362 Hom.: 9103

Bravo AF: 0.307

Asia WGS AF: 0.584 AC: 2020 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.97

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6123837; hg19: chr20-57465571;