rs397514456

Positions:

• chr20-58910818-G-A
• chr20-58910818-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_000516.7(GNAS):​c.1174G>A​(p.Glu392Lys) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.52

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 12 ACMG points.

• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769
• PP5: Variant 20-58910818-G-A is Pathogenic according to our data. Variant chr20-58910818-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58910818-G-A is described in Lovd as [Likely_pathogenic]. Variant chr20-58910818-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_080425.4	c.3103G>A	p.Glu1035Lys	missense_variant	13/13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7	c.1174G>A	p.Glu392Lys	missense_variant	13/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*1080G>A		3_prime_UTR_variant	13/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371100.9	c.3103G>A	p.Glu1035Lys	missense_variant	13/13	5	NM_080425.4	ENSP00000360141
GNAS	ENST00000371085.8	c.1174G>A	p.Glu392Lys	missense_variant	13/13	1	NM_000516.7	ENSP00000360126
GNAS	ENST00000371075.7	c.*1080G>A		3_prime_UTR_variant	13/13	1	NM_016592.5	ENSP00000360115

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 21, 2020	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects GNAS protein function (PMID: 21488135). This variant has been observed in individual(s) with pseudohypoparathyroidism and pseudopseudohypoparathyroidism (PMID: 12970262, 21488135, 24651309, 21525160). ClinVar contains an entry for this variant (Variation ID: 29747). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 392 of the GNAS protein (p.Glu392Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -

Pseudohypoparathyroidism type 1C Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;.;.;T;.;.;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.1	.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.019	D;D;T;T;T;T;.
Sift4G	Uncertain	0.051	T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;P;.;P;.
Vest4		0.78
MutPred		0.57		Gain of MoRF binding (P = 0);.;.;.;.;.;.;
MVP		0.98
MPC		3.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.65
gMVP		0.96

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: rs397514456; hg19: chr20-57485873; COSMIC: COSV55681751; COSMIC: COSV55681751;