20-58900136-A-G

Position:

• chr20-58900136-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.257+1151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 570,298 control chromosomes in the GnomAD database, including 154,321 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 0.77 (45786 hom., cov: 30)
  • Exomes 𝑓: 0.72 (108535 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_000516.7	c.257+1151A>G		intron_variant		ENST00000371085.8
GNAS	NM_016592.5	c.*160+1151A>G		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2186+1151A>G		intron_variant		ENST00000371100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*160+1151A>G		intron_variant		1	NM_016592.5
GNAS	ENST00000371085.8	c.257+1151A>G		intron_variant		1	NM_000516.7
GNAS	ENST00000371100.9	c.2186+1151A>G		intron_variant		5	NM_080425.4

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116827 AN: 151866 Hom.: 45730 Cov.: 30

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.707

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.771

GnomAD4 exome AF: 0.717 AC: 299944 AN: 418314 Hom.: 108535 Cov.: 0 AF XY: 0.718 AC XY: 158837 AN XY: 221208

Gnomad4 AFR exome AF: 0.932

Gnomad4 AMR exome AF: 0.740

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.685

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.705

Gnomad4 OTH exome AF: 0.732

GnomAD4 genome AF: 0.769 AC: 116941 AN: 151984 Hom.: 45786 Cov.: 30 AF XY: 0.768 AC XY: 57057 AN XY: 74292

Gnomad4 AFR AF: 0.925

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.726

Gnomad4 SAS AF: 0.758

Gnomad4 FIN AF: 0.696

Gnomad4 NFE AF: 0.702

Gnomad4 OTH AF: 0.774

Alfa AF: 0.719 Hom.: 71635

Bravo AF: 0.783

Asia WGS AF: 0.784 AC: 2727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13831; hg19: chr20-57475191;