chr20-58840055-A-G

Position:

• chr20-58840055-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016592.5(GNAS):​c.-52A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,596,376 control chromosomes in the GnomAD database, including 329,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26724 hom., cov: 29)
  • Exomes 𝑓: 0.64 (302495 hom.)
• Consequence: GNAS NM_016592.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0540

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-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 20-58840055-A-G is Benign according to our data. Variant chr20-58840055-A-G is described in ClinVar as [Benign]. Clinvar id is 1280334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_016592.5	c.-52A>G		5_prime_UTR_variant	1/13	ENST00000371075.7
GNAS-AS1	NR_002785.2	n.819+1882T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.-52A>G		5_prime_UTR_variant	1/13	1	NM_016592.5
GNAS-AS1	ENST00000424094.6	n.819+1882T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88299 AN: 151000 Hom.: 26697 Cov.: 29

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.559

GnomAD4 exome AF: 0.645 AC: 931470 AN: 1445258 Hom.: 302495 Cov.: 32 AF XY: 0.645 AC XY: 464481 AN XY: 719630

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.674

Gnomad4 ASJ exome AF: 0.508

Gnomad4 EAS exome AF: 0.777

Gnomad4 SAS exome AF: 0.685

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.645

Gnomad4 OTH exome AF: 0.626

GnomAD4 genome AF: 0.585 AC: 88376 AN: 151118 Hom.: 26724 Cov.: 29 AF XY: 0.590 AC XY: 43547 AN XY: 73852

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.597

Gnomad4 ASJ AF: 0.513

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.683

Gnomad4 FIN AF: 0.695

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.565

Alfa AF: 0.614 Hom.: 27483

Bravo AF: 0.570

Asia WGS AF: 0.709 AC: 2464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.69

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800900; hg19: chr20-57415110; COSMIC: COSV100005868; COSMIC: COSV100005868;