rs6026593

Positions:

• chr20-58904078-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000371085.8(GNAS):​c.432+287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,182 control chromosomes in the GnomAD database, including 3,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3896 hom., cov: 32)
• Consequence: GNAS ENST00000371085.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.118

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-58904078-A-G is Benign according to our data. Variant chr20-58904078-A-G is described in ClinVar as [Benign]. Clinvar id is 1236136.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.432+287A>G		intron_variant		ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*338+287A>G		intron_variant		ENST00000371075.7	NP_057676.1
GNAS	NM_080425.4	c.2361+287A>G		intron_variant		ENST00000371100.9	NP_536350.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.*338+287A>G		intron_variant		1	NM_016592.5	ENSP00000360115
GNAS	ENST00000371085.8	c.432+287A>G		intron_variant		1	NM_000516.7	ENSP00000360126
GNAS	ENST00000371100.9	c.2361+287A>G		intron_variant		5	NM_080425.4	ENSP00000360141

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28465 AN: 152064 Hom.: 3877 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.188 AC: 28542 AN: 152182 Hom.: 3896 Cov.: 32 AF XY: 0.184 AC XY: 13677 AN XY: 74408

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.134

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0951

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.191

Alfa AF: 0.121 Hom.: 1901

Bravo AF: 0.199

Asia WGS AF: 0.192 AC: 665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.79

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

Other links and lift over

dbSNP: rs6026593; hg19: chr20-57479133;