20-58909991-C-A

Variant names:

• chr20-58909991-C-A
• NM_000516.7:c.880C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000516.7(GNAS):​c.880C>A​(p.Gln294Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41

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 Uncertain_significance. Variant got 4 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, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.880C>A	p.Gln294Lys	missense_variant	Exon 11 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*786C>A		3_prime_UTR_variant	Exon 11 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.880C>A	p.Gln294Lys	missense_variant	Exon 11 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2812C>A	p.Gln938Lys	missense_variant	Exon 11 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2767C>A	p.Gln923Lys	missense_variant	Exon 10 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.883C>A	p.Gln295Lys	missense_variant	Exon 11 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.838C>A	p.Gln280Lys	missense_variant	Exon 10 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.706C>A	p.Gln236Lys	missense_variant	Exon 11 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.706C>A	p.Gln236Lys	missense_variant	Exon 12 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.706C>A	p.Gln236Lys	missense_variant	Exon 11 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 10 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 11 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 10 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 10 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 10 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 10 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.661C>A	p.Gln221Lys	missense_variant	Exon 10 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*786C>A		3_prime_UTR_variant	Exon 11 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*741C>A		3_prime_UTR_variant	Exon 10 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.;.;D;.;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.2	.;.;.;L;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;.
REVEL	Pathogenic	0.73
Sift	Benign	0.17	T;T;T;T;T;T;.
Sift4G	Benign	0.43	T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;D;.;D;.
Vest4		0.63
MutPred		0.61		Gain of ubiquitination at Q937 (P = 0.0258);.;.;.;.;.;.;
MVP		0.98
MPC		3.5
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-57485046;