rs1555889031

Positions:

• chr20-58903708-G-A
• chr20-58903708-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000516.7(GNAS):​c.349G>A​(p.Val117Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V117G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.59

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58903709-T-G is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 20-58903708-G-A is Pathogenic according to our data. Variant chr20-58903708-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445504.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.2278G>A	p.Val760Met	missense_variant	5/13	ENST00000371100.9
GNAS	NM_000516.7	c.349G>A	p.Val117Met	missense_variant	5/13	ENST00000371085.8
GNAS	NM_016592.5	c.*255G>A		3_prime_UTR_variant	5/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.2278G>A	p.Val760Met	missense_variant	5/13	5	NM_080425.4
GNAS	ENST00000371085.8	c.349G>A	p.Val117Met	missense_variant	5/13	1	NM_000516.7
GNAS	ENST00000371075.7	c.*255G>A		3_prime_UTR_variant	5/13	1	NM_016592.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 22, 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 445504). 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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 117 of the GNAS protein (p.Val117Met). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;.;D;.;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;.;D;.
Vest4		0.48
MutPred		0.52		Loss of helix (P = 0.0558);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.79

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: rs1555889031; hg19: chr20-57478763; COSMIC: COSV55675652; COSMIC: COSV55675652;