rs148033592

Positions:

• chr20-58854641-C-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+13755C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,505,282 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (4 hom., cov: 33)
  • Exomes 𝑓: 0.015 (6 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.480

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024326742).
• BP6: Variant 20-58854641-C-G is Benign according to our data. Variant chr20-58854641-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 134480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58854641-C-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.1376C>G	p.Pro459Arg	missense_variant	1/13	ENST00000371100.9
GNAS	NM_016592.5	c.*42+13755C>G		intron_variant		ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.1376C>G	p.Pro459Arg	missense_variant	1/13	5	NM_080425.4
GNAS	ENST00000371075.7	c.*42+13755C>G		intron_variant		1	NM_016592.5

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1577 AN: 149672 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00409

Gnomad SAS AF: 0.00795

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00980

Gnomad NFE AF: 0.00383

Gnomad OTH AF: 0.00920

GnomAD3 exomes AF: 0.00947 AC: 1187 AN: 125312 Hom.: 1 AF XY: 0.00972 AC XY: 669 AN XY: 68834

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00303

Gnomad SAS exome AF: 0.0133

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00662

Gnomad OTH exome AF: 0.00889

GnomAD4 exome AF: 0.0148 AC: 20063 AN: 1355510 Hom.: 6 Cov.: 34 AF XY: 0.0143 AC XY: 9580 AN XY: 669260

Gnomad4 AFR exome AF: 0.0885

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00175

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.000650

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0106 AC: 1586 AN: 149772 Hom.: 4 Cov.: 33 AF XY: 0.0104 AC XY: 759 AN XY: 73294

Gnomad4 AFR AF: 0.0286

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00410

Gnomad4 SAS AF: 0.00796

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00383

Gnomad4 OTH AF: 0.00960

Alfa AF: 0.0356 Hom.: 1

ExAC AF: 0.00410 AC: 325

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2018	This variant is associated with the following publications: (PMID: 30022773) -

not specified Benign:1 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

GNAS-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.4
DANN	Benign	0.97
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.085	N
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.024
Sift	Benign	0.10	T
Sift4G	Benign	0.50	T
Vest4		0.097
MVP		0.21
ClinPred		0.0055	T
GERP RS		0.082

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs148033592; hg19: chr20-57429696; COSMIC: COSV58326923; COSMIC: COSV58326923;