rs137854536

Positions:

• chr20-58909737-CG-GC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_000516.7(GNAS):​c.772_773delCGinsGC​(p.Arg258Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.47

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]

GNAS (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a mutagenesis_site Increases GDP release and impairs receptor-mediated activation; markedly elevated intrinsic GTPase rate which will lead to more rapid inactivation. (size 0) in uniprot entity GNAS2_HUMAN there are 5 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 chr20-58909738-G-A is described in Lovd as [Likely_pathogenic].
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 20-58909737-CG-GC is Pathogenic according to our data. Variant chr20-58909737-CG-GC is described in ClinVar as [Pathogenic]. Clinvar id is 15942.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.772_773delCGinsGC	p.Arg258Ala	missense_variant		ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*678_*679delCGinsGC		3_prime_UTR_variant	10/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.772_773delCGinsGC	p.Arg258Ala	missense_variant		1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2704_2705delCGinsGC	p.Arg902Ala	missense_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2659_2660delCGinsGC	p.Arg887Ala	missense_variant		5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.775_776delCGinsGC	p.Arg259Ala	missense_variant		1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.730_731delCGinsGC	p.Arg244Ala	missense_variant		1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.598_599delCGinsGC	p.Arg200Ala	missense_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.598_599delCGinsGC	p.Arg200Ala	missense_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.598_599delCGinsGC	p.Arg200Ala	missense_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.553_554delCGinsGC	p.Arg185Ala	missense_variant		3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*678_*679delCGinsGC		3_prime_UTR_variant	10/13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*633_*634delCGinsGC		3_prime_UTR_variant	9/12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pseudopseudohypoparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 13, 1999

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854536; hg19: chr20-57484792;