20-58884756-C-T

Position:

• chr20-58884756-C-T

Variant summary

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

The NM_016592.5(GNAS):​c.*43-10856C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 152,116 control chromosomes in the GnomAD database, including 26,819 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 0.59 (26819 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.430

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]

ENSG00000225806 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*43-10856C>T		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.*43-10856C>T		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-10856C>T		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-10856C>T		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000663479.2	c.-38-10856C>T		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-10856C>T		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-10856C>T		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000453292.7	c.*43-10856C>T		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.586 AC: 89097 AN: 151994 Hom.: 26798 Cov.: 33

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.633

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.609

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.586 AC: 89159 AN: 152112 Hom.: 26819 Cov.: 33 AF XY: 0.590 AC XY: 43896 AN XY: 74352

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.613

Alfa AF: 0.614 Hom.: 9499

Bravo AF: 0.583

Asia WGS AF: 0.730 AC: 2540 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4810149; hg19: chr20-57459811;