20-58896988-A-G

Position:

• chr20-58896988-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000516.7(GNAS):​c.212+1304A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 152,128 control chromosomes in the GnomAD database, including 38,074 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 0.70 (38074 hom., cov: 32)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.610

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.212+1304A>G		intron_variant		ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*115+1304A>G		intron_variant		ENST00000371075.7	NP_057676.1
GNAS	NM_080425.4	c.2141+1304A>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.*115+1304A>G		intron_variant		1	NM_016592.5	ENSP00000360115
GNAS	ENST00000371085.8	c.212+1304A>G		intron_variant		1	NM_000516.7	ENSP00000360126
GNAS	ENST00000371100.9	c.2141+1304A>G		intron_variant		5	NM_080425.4	ENSP00000360141

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107119 AN: 152010 Hom.: 38036 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.702

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

GnomAD4 genome AF: 0.705 AC: 107215 AN: 152128 Hom.: 38074 Cov.: 32 AF XY: 0.706 AC XY: 52543 AN XY: 74384

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.698

Gnomad4 ASJ AF: 0.689

Gnomad4 EAS AF: 0.748

Gnomad4 SAS AF: 0.758

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.657

Gnomad4 OTH AF: 0.705

Alfa AF: 0.674 Hom.: 64721

Bravo AF: 0.711

Asia WGS AF: 0.783 AC: 2721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.63

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: rs2057291; hg19: chr20-57472043;