chr20-58839812-C-G

Position:

• chr20-58839812-C-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.-295C>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 0.0379 in 585,262 control chromosomes in the GnomAD database, including 879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (529 hom., cov: 32)
  • Exomes 𝑓: 0.030 (350 hom.)
• Consequence: GNAS NM_016592.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.886

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=-0.81).
• BP6: Variant 20-58839812-C-G is Benign according to our data. Variant chr20-58839812-C-G is described in ClinVar as [Benign]. Clinvar id is 1282105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.-295C>G		5_prime_UTR_variant	1/13	ENST00000371075.7	NP_057676.1
GNAS-AS1	NR_002785.2	n.819+2125G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.-295C>G		5_prime_UTR_variant	1/13	1	NM_016592.5	ENSP00000360115
GNAS-AS1	ENST00000424094.6	n.819+2125G>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9096 AN: 152180 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0554

GnomAD4 exome AF: 0.0301 AC: 13037 AN: 432964 Hom.: 350 Cov.: 0 AF XY: 0.0303 AC XY: 6856 AN XY: 226562

Gnomad4 AFR exome AF: 0.146

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.00238

Gnomad4 SAS exome AF: 0.0416

Gnomad4 FIN exome AF: 0.0118

Gnomad4 NFE exome AF: 0.0288

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0600 AC: 9136 AN: 152298 Hom.: 529 Cov.: 32 AF XY: 0.0572 AC XY: 4258 AN XY: 74476

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0323

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00772

Gnomad4 SAS AF: 0.0418

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0299

Gnomad4 OTH AF: 0.0653

Alfa AF: 0.0161 Hom.: 9

Bravo AF: 0.0648

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	Nov 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61558260; hg19: chr20-57414867;