NM_000516.7:c.1174G>A

Variant names:

• chr20-58910818-G-A
• rs397514456
• NM_000516.7:c.1174G>A

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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 the GNAS gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 64 curated benign missense variants. Gene score misZ: 2.6546 (below the threshold of 3.09). Trascript score misZ: 4.8361 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 [Likely_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 rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.1174G>A	p.Glu392Lys	missense_variant	Exon 13 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*1080G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.1174G>A	p.Glu392Lys	missense_variant	Exon 13 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.3106G>A	p.Glu1036Lys	missense_variant	Exon 13 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.3061G>A	p.Glu1021Lys	missense_variant	Exon 12 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.1177G>A	p.Glu393Lys	missense_variant	Exon 13 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.1132G>A	p.Glu378Lys	missense_variant	Exon 12 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.1000G>A	p.Glu334Lys	missense_variant	Exon 13 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.1000G>A	p.Glu334Lys	missense_variant	Exon 14 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.1000G>A	p.Glu334Lys	missense_variant	Exon 13 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 12 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 13 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 12 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 12 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 12 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 12 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.955G>A	p.Glu319Lys	missense_variant	Exon 12 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*1080G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*1035G>A		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 10, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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. This variant is not present in population databases (ExAC no frequency). Experimental studies have shown that this variant affects GNAS protein function (PMID: 21488135). For these reasons, this variant has been classified as Pathogenic. -

Pseudohypoparathyroidism type 1C Pathogenic:1

Jun 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pseudohypoparathyroidism type I A Pathogenic:1

Sep 01, 2024

Suzhou Clinical Center for Rare Diseases in Children, Children's Hospital of Soochow University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000516.7:c.1174G>A (p.Glu392Lys) variant of GNAS is a missense variant that has been reported in the literature to have a higher frequency in patients compared to the control group, and this variant has been detected in multiple unrelated patients (PMID: 24651309, 21525160, 21488135,12970262) (PS4). The gnomAD database does not include this variant's frequency in the population (PM2_Supproting). Revel score is 0.84 (PP3_Moderate). According to the ACMG guidelines, this variant is classified as pathogenic (PS4 + PM2_Supporting + PP3_Moderate). -

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;.;.;.
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;