rs137854532

Variant names:

• chr20-58905443-C-A
• NM_000516.7:c.493C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58905443-C-A
• chr20-58905443-C-G
• chr20-58905443-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000516.7(GNAS):​c.493C>A​(p.Arg165Ser) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.16

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 4) in uniprot entity GNAS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr20-58905443-C-T is described in Lovd as [Pathogenic].
• 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, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.493C>A	p.Arg165Ser	missense_variant	Exon 6 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*399C>A		3_prime_UTR_variant	Exon 6 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.493C>A	p.Arg165Ser	missense_variant	Exon 6 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2425C>A	p.Arg809Ser	missense_variant	Exon 6 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2380C>A	p.Arg794Ser	missense_variant	Exon 5 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.496C>A	p.Arg166Ser	missense_variant	Exon 6 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.451C>A	p.Arg151Ser	missense_variant	Exon 5 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.319C>A	p.Arg107Ser	missense_variant	Exon 6 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.319C>A	p.Arg107Ser	missense_variant	Exon 7 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.319C>A	p.Arg107Ser	missense_variant	Exon 6 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 5 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 6 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 5 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 5 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 5 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 5 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.274C>A	p.Arg92Ser	missense_variant	Exon 5 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*399C>A		3_prime_UTR_variant	Exon 6 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*354C>A		3_prime_UTR_variant	Exon 5 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;D;.;.;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;.;H;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;.;D;.
Vest4		0.86
MutPred		0.73		Gain of phosphorylation at Y812 (P = 0.1196);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		3.3
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.95

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: chr20-57480498;