rs3730168

chr20-58903884-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000516.7(GNAS):c.432+93G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,361,808 control chromosomes in the GnomAD database, including 75,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (9821 hom., cov: 32)
  • Exomes 𝑓: 0.33 (65522 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.788

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-58903884-G-A is Benign according to our data. Variant chr20-58903884-G-A is described in ClinVar as [Benign]. Clinvar id is 1238617.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_000516.7	c.432+93G>A		intron_variant		ENST00000371085.8
GNAS	NM_016592.5	c.*338+93G>A		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2361+93G>A		intron_variant		ENST00000371100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*338+93G>A		intron_variant		1	NM_016592.5
GNAS	ENST00000371085.8	c.432+93G>A		intron_variant		1	NM_000516.7
GNAS	ENST00000371100.9	c.2361+93G>A		intron_variant		5	NM_080425.4

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53636 AN: 151976 Hom.: 9803 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.325 AC: 393706 AN: 1209714 Hom.: 65522 AF XY: 0.326 AC XY: 200045 AN XY: 613274

Gnomad4 AFR exome AF: 0.461

Gnomad4 AMR exome AF: 0.306

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.287

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.324

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.353 AC: 53689 AN: 152094 Hom.: 9821 Cov.: 32 AF XY: 0.350 AC XY: 26032 AN XY: 74340

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.266

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.336

Alfa AF: 0.321 Hom.: 11070

Bravo AF: 0.358

Asia WGS AF: 0.282 AC: 979 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.22
Dann	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3730168; hg19: chr20-57478939; COSMIC: COSV55673083; COSMIC: COSV55673083;