20-58840940-A-G

Position:

• chr20-58840940-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.*42+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,583,672 control chromosomes in the GnomAD database, including 324,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26538 hom., cov: 31)
  • Exomes 𝑓: 0.64 (298373 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.631

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=-0.88).
• BP6: Variant 20-58840940-A-G is Benign according to our data. Variant chr20-58840940-A-G is described in ClinVar as [Benign]. Clinvar id is 1273639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*42+54A>G		intron_variant		ENST00000371075.7	NP_057676.1
GNAS-AS1	NR_002785.2	n.819+997T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.*42+54A>G		intron_variant		1	NM_016592.5	ENSP00000360115
GNAS-AS1	ENST00000424094.6	n.819+997T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 87904 AN: 151750 Hom.: 26514 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.643 AC: 920601 AN: 1431804 Hom.: 298373 AF XY: 0.644 AC XY: 458657 AN XY: 712202

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.670

Gnomad4 ASJ exome AF: 0.507

Gnomad4 EAS exome AF: 0.776

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.690

Gnomad4 NFE exome AF: 0.644

Gnomad4 OTH exome AF: 0.624

GnomAD4 genome AF: 0.579 AC: 87978 AN: 151868 Hom.: 26538 Cov.: 31 AF XY: 0.584 AC XY: 43366 AN XY: 74224

Gnomad4 AFR AF: 0.421

Gnomad4 AMR AF: 0.595

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.802

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.691

Gnomad4 NFE AF: 0.634

Gnomad4 OTH AF: 0.560

Alfa AF: 0.602 Hom.: 3517

Bravo AF: 0.567

Asia WGS AF: 0.708 AC: 2458 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	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.35

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800905; hg19: chr20-57415995;