rs3730170

Positions:

• chr20-58905365-T-C

Variant summary

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

The NM_000516.7(GNAS):​c.433-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,427,932 control chromosomes in the GnomAD database, including 1,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (678 hom., cov: 32)
  • Exomes 𝑓: 0.026 (973 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.730

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-58905365-T-C is Benign according to our data. Variant chr20-58905365-T-C is described in ClinVar as [Benign]. Clinvar id is 198088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58905365-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.433-18T>C		intron_variant		ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*339-18T>C		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.433-18T>C		intron_variant		1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*339-18T>C		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2365-18T>C		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2320-18T>C		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.436-18T>C		intron_variant		1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.391-18T>C		intron_variant		1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.259-18T>C		intron_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.259-18T>C		intron_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.259-18T>C		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.214-18T>C		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.214-18T>C		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.214-18T>C		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.214-18T>C		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.214-18T>C		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.214-18T>C		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.214-18T>C		intron_variant		3		ENSP00000499443.2
GNAS	ENST00000453292.7	c.*294-18T>C		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10229 AN: 152124 Hom.: 676 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0597

GnomAD3 exomes AF: 0.0345 AC: 8665 AN: 251376 Hom.: 365 AF XY: 0.0314 AC XY: 4264 AN XY: 135866

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0318

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.0356

Gnomad SAS exome AF: 0.0189

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0384

GnomAD4 exome AF: 0.0262 AC: 33465 AN: 1275690 Hom.: 973 Cov.: 20 AF XY: 0.0257 AC XY: 16570 AN XY: 644162

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.0268

Gnomad4 EAS exome AF: 0.0502

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0397

GnomAD4 genome AF: 0.0673 AC: 10248 AN: 152242 Hom.: 678 Cov.: 32 AF XY: 0.0656 AC XY: 4884 AN XY: 74468

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0489

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.0417

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0595

Alfa AF: 0.0415 Hom.: 98

Bravo AF: 0.0749

Asia WGS AF: 0.0520 AC: 181 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.67

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: rs3730170; hg19: chr20-57480420; COSMIC: COSV55673089; COSMIC: COSV55673089;