rs587778381

Positions:

• chr20-58903532-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000516.7(GNAS):​c.259G>A​(p.Glu87Lys) variant causes a missense, splice region 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. 12/21 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAS NM_000516.7 missense, splice_region
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.79

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 7 ACMG points.

• PM1: In a helix (size 24) in uniprot entity GNAS2_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000516.7
• 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, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_080425.4	c.2188G>A	p.Glu730Lys	missense_variant, splice_region_variant	4/13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7	c.259G>A	p.Glu87Lys	missense_variant, splice_region_variant	4/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*165G>A		3_prime_UTR_variant	4/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371100.9	c.2188G>A	p.Glu730Lys	missense_variant, splice_region_variant	4/13	5	NM_080425.4	ENSP00000360141
GNAS	ENST00000371085.8	c.259G>A	p.Glu87Lys	missense_variant, splice_region_variant	4/13	1	NM_000516.7	ENSP00000360126
GNAS	ENST00000371075.7	c.*165G>A		3_prime_UTR_variant	4/13	1	NM_016592.5	ENSP00000360115

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;D;.;.;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;T;D;D;D;T;T;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;.;.;.;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;N;D;.;N;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;D;D;.;T;D;D;D;.
Sift4G	Uncertain	0.030	D;D;T;T;T;T;D;D;T
Polyphen		0.91	P;.;.;.;.;P;.;P;.
Vest4		0.70
MutPred		0.63		Gain of MoRF binding (P = 0.0041);.;.;.;.;.;.;.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587778381; hg19: chr20-57478587;