20-58888417-C-G

Position:

• chr20-58888417-C-G

Variant summary

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

The NM_016592.5(GNAS):​c.*43-7195C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 152,136 control chromosomes in the GnomAD database, including 28,252 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 0.61 (28245 hom., cov: 32)
  • Exomes 𝑓: 0.59 (7 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*43-7195C>G		intron_variant		ENST00000371075.7	NP_057676.1
GNAS	NM_080425.4	c.2069-7195C>G		intron_variant		ENST00000371100.9	NP_536350.2
LOC101927932	NR_126334.1	n.37+357G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.*43-7195C>G		intron_variant		1	NM_016592.5	ENSP00000360115
GNAS	ENST00000371100.9	c.2069-7195C>G		intron_variant		5	NM_080425.4	ENSP00000360141
	ENST00000441270.6	n.19+357G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92070 AN: 151974 Hom.: 28224 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.624

GnomAD4 exome AF: 0.591 AC: 26 AN: 44 Hom.: 7 Cov.: 0 AF XY: 0.607 AC XY: 17 AN XY: 28

Gnomad4 AFR exome AF: 0.500

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.606 AC: 92132 AN: 152092 Hom.: 28245 Cov.: 32 AF XY: 0.609 AC XY: 45296 AN XY: 74332

Gnomad4 AFR AF: 0.513

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.664

Gnomad4 EAS AF: 0.743

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.647

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.628

Alfa AF: 0.532 Hom.: 1670

Bravo AF: 0.605

Asia WGS AF: 0.745 AC: 2591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.40

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6026578; hg19: chr20-57463472;