20-58898945-G-T

Position:

• chr20-58898945-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000516.7(GNAS):​c.217G>T​(p.Gly73Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G73G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Neuroendocrine secretory protein 55 (size 198) in uniprot entity GNAS3_HUMAN there are 67 pathogenic changes around while only 1 benign (99%) in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAS. . Gene score misZ 2.6546 (greater than the threshold 3.09). Trascript score misZ 4.8361 (greater than threshold 3.09). GenCC has associacion of gene with ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38053524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.217G>T	p.Gly73Cys	missense_variant	3/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*120G>T		3_prime_UTR_variant	3/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.217G>T	p.Gly73Cys	missense_variant	3/13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2146G>T	p.Gly716Cys	missense_variant	3/13			ENSP00000504675.2
GNAS	ENST00000354359.12	c.217G>T	p.Gly73Cys	missense_variant	3/13	1		ENSP00000346328.7
GNAS	ENST00000470512.6	c.40G>T	p.Gly14Cys	missense_variant	3/13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.40G>T	p.Gly14Cys	missense_variant	4/14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.40G>T	p.Gly14Cys	missense_variant	3/13			ENSP00000499353.2
GNAS	ENST00000371075.7	c.*120G>T		3_prime_UTR_variant	3/13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000371102.8	c.2141+3261G>T		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000371095.7	c.212+3261G>T		intron_variant		1		ENSP00000360136.3
GNAS	ENST00000462499.6	c.35+3261G>T		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.35+3261G>T		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.35+3261G>T		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.35+3261G>T		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.35+3261G>T		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.35+3261G>T		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.35+3261G>T		intron_variant		3		ENSP00000499443.2
GNAS	ENST00000461152.6	c.*124+3261G>T		intron_variant		5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*115+3261G>T		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461400 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 727070

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNAS protein function. This variant has not been reported in the literature in individuals affected with GNAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 73 of the GNAS protein (p.Gly73Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;D;.;T;T
Eigen	Benign	0.057
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.71	T;D;D;D;D;T;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	-1.2	.;.;.;N;N;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N;N;.;N;N;D;.
REVEL	Uncertain	0.54
Sift	Benign	0.072	T;T;.;T;D;D;.
Sift4G	Benign	0.066	T;T;D;T;T;T;D
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.76
MutPred		0.49		Gain of helix (P = 0.0325);.;.;.;.;.;.;
MVP		0.97
MPC		1.3
ClinPred		0.96	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587778380; hg19: chr20-57474000;