20-58909186-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000516.7(GNAS):c.555C>T(p.Ile185=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,874 control chromosomes in the GnomAD database, including 2,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1313 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1308 hom.)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.27

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 20-58909186-C-T is Benign according to our data. Variant chr20-58909186-C-T is described in ClinVar as [Benign]. Clinvar id is 1166173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58909186-C-T is described in Lovd as [Benign]. Variant chr20-58909186-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.2484C>T	p.Ile828=	synonymous_variant	7/13	ENST00000371100.9
GNAS	NM_000516.7	c.555C>T	p.Ile185=	synonymous_variant	7/13	ENST00000371085.8
GNAS	NM_016592.5	c.*461C>T		3_prime_UTR_variant	7/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.2484C>T	p.Ile828=	synonymous_variant	7/13	5	NM_080425.4
GNAS	ENST00000371085.8	c.555C>T	p.Ile185=	synonymous_variant	7/13	1	NM_000516.7
GNAS	ENST00000371075.7	c.*461C>T		3_prime_UTR_variant	7/13	1	NM_016592.5

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11885 AN: 152072 Hom.: 1310 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0277 AC: 6968 AN: 251482 Hom.: 543 AF XY: 0.0232 AC XY: 3148 AN XY: 135918

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0185 AC: 26974 AN: 1461684 Hom.: 1308 Cov.: 31 AF XY: 0.0176 AC XY: 12792 AN XY: 727134

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0266

GnomAD4 genome AF: 0.0783 AC: 11909 AN: 152190 Hom.: 1313 Cov.: 32 AF XY: 0.0755 AC XY: 5623 AN XY: 74432

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0324

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.0563

Alfa AF: 0.0304 Hom.: 350

Bravo AF: 0.0875

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	16
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs8620; hg19: chr20-57484241; COSMIC: COSV99671336; COSMIC: COSV99671336;