20-58888938-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.*43-6674C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 274,276 control chromosomes in the GnomAD database, including 61,217 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 0.67 (33224 hom., cov: 31)
  • Exomes 𝑓: 0.67 (27993 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21

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=-0.73).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_016592.5	c.*43-6674C>T		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2069-6674C>T		intron_variant		ENST00000371100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*43-6674C>T		intron_variant		1	NM_016592.5
GNAS	ENST00000371100.9	c.2069-6674C>T		intron_variant		5	NM_080425.4

Frequencies

GnomAD3 genomes AF: 0.665 AC: 99362 AN: 149346 Hom.: 33194 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.667 AC: 83245 AN: 124826 Hom.: 27993 Cov.: 4 AF XY: 0.668 AC XY: 39613 AN XY: 59296

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.734

Gnomad4 ASJ exome AF: 0.749

Gnomad4 EAS exome AF: 0.758

Gnomad4 SAS exome AF: 0.745

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.664

Gnomad4 OTH exome AF: 0.683

GnomAD4 genome AF: 0.665 AC: 99431 AN: 149450 Hom.: 33224 Cov.: 31 AF XY: 0.669 AC XY: 48799 AN XY: 72954

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.691

Gnomad4 EAS AF: 0.748

Gnomad4 SAS AF: 0.757

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.680

Alfa AF: 0.650 Hom.: 7881

Bravo AF: 0.665

Asia WGS AF: 0.753 AC: 2570 AN: 3412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	8.0
Dann	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6026579; hg19: chr20-57463993;