20-58840400-C-T

Position:

• chr20-58840400-C-T

Variant summary

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

The NM_001410912.1(GNAS):​c.-444C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,613,458 control chromosomes in the GnomAD database, including 1,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.048 (283 hom., cov: 32)
  • Exomes 𝑓: 0.031 (940 hom.)
• Consequence: GNAS NM_001410912.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.125

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:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-58840400-C-T is Benign according to our data. Variant chr20-58840400-C-T is described in ClinVar as [Benign]. Clinvar id is 1205855.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-58840400-C-T is described in Lovd as [Benign]. Variant chr20-58840400-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.294C>T	p.Pro98Pro	synonymous_variant	1/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.294C>T	p.Pro98Pro	synonymous_variant	1/13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.294C>T	p.Pro98Pro	synonymous_variant	1/12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7284 AN: 152114 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00774

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0301 AC: 7510 AN: 249632 Hom.: 177 AF XY: 0.0300 AC XY: 4053 AN XY: 135198

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00517

Gnomad SAS exome AF: 0.0411

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0314 AC: 45843 AN: 1461226 Hom.: 940 Cov.: 36 AF XY: 0.0315 AC XY: 22930 AN XY: 726956

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.00302

Gnomad4 SAS exome AF: 0.0409

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0345

GnomAD4 genome AF: 0.0481 AC: 7322 AN: 152232 Hom.: 283 Cov.: 32 AF XY: 0.0456 AC XY: 3397 AN XY: 74454

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00775

Gnomad4 SAS AF: 0.0417

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0545

Alfa AF: 0.0359 Hom.: 78

Bravo AF: 0.0511

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800902; hg19: chr20-57415455; COSMIC: COSV58330333; COSMIC: COSV58330333;