20-58900136-A-G

Variant names:

• chr20-58900136-A-G
• rs13831
• ENST00000481768.6:n.*273A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000481768.6(GNAS):​n.*273A>G variant causes a non coding transcript exon 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 ENST00000481768.6 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 42 publications found

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 Gene-Disease associations (from GenCC):

• McCune-Albright syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• progressive osseous heteroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudohypoparathyroidism type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudopseudohypoparathyroidism

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• pseudohypoparathyroidism type 1A

  Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000481768.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2186+1151A>G		intron	N/A	NP_536350.2
	GNAS	NM_000516.7	MANE Select	c.257+1151A>G		intron	N/A	NP_000507.1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*160+1151A>G		intron	N/A	NP_057676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000481768.6	TSL:1	n.*273A>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000499644.2
	GNAS	ENST00000481768.6	TSL:1	n.*273A>G		3_prime_UTR	Exon 6 of 6	ENSP00000499644.2
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2186+1151A>G		intron	N/A	ENSP00000360141.3

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

African (AFR) AF: 0.932 AC: 10431 AN: 11194

American (AMR) AF: 0.740 AC: 11674 AN: 15778

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 9503 AN: 12916

East Asian (EAS) AF: 0.685 AC: 19789 AN: 28890

South Asian (SAS) AF: 0.745 AC: 29964 AN: 40244

European-Finnish (FIN) AF: 0.699 AC: 21544 AN: 30806

Middle Eastern (MID) AF: 0.735 AC: 1526 AN: 2076

European-Non Finnish (NFE) AF: 0.705 AC: 177607 AN: 251934

Other (OTH) AF: 0.732 AC: 17906 AN: 24476

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

African (AFR) AF: 0.925 AC: 38363 AN: 41470

American (AMR) AF: 0.731 AC: 11156 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2519 AN: 3466

East Asian (EAS) AF: 0.726 AC: 3751 AN: 5164

South Asian (SAS) AF: 0.758 AC: 3651 AN: 4816

European-Finnish (FIN) AF: 0.696 AC: 7336 AN: 10538

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.702 AC: 47675 AN: 67952

Other (OTH) AF: 0.774 AC: 1633 AN: 2110

Alfa AF: 0.729 Hom.: 161293

Bravo AF: 0.783

Asia WGS AF: 0.784 AC: 2727 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.46
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13831; hg19: chr20-57475191;