20-58909540-C-T

Variant names:

• chr20-58909540-C-T
• NM_000516.7:c.679C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000516.7(GNAS):​c.679C>T​(p.Gln227*) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.47

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58909540-C-T is Pathogenic according to our data. Variant chr20-58909540-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1459843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.679C>T	p.Gln227*	stop_gained	Exon 9 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*585C>T		3_prime_UTR_variant	Exon 9 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.679C>T	p.Gln227*	stop_gained	Exon 9 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2611C>T	p.Gln871*	stop_gained	Exon 9 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2566C>T	p.Gln856*	stop_gained	Exon 8 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.682C>T	p.Gln228*	stop_gained	Exon 9 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.637C>T	p.Gln213*	stop_gained	Exon 8 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.505C>T	p.Gln169*	stop_gained	Exon 9 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.505C>T	p.Gln169*	stop_gained	Exon 10 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.505C>T	p.Gln169*	stop_gained	Exon 9 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.460C>T	p.Gln154*	stop_gained	Exon 8 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.460C>T	p.Gln154*	stop_gained	Exon 9 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.460C>T	p.Gln154*	stop_gained	Exon 8 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.460C>T	p.Gln154*	stop_gained	Exon 8 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.460C>T	p.Gln154*	stop_gained	Exon 8 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.460C>T	p.Gln154*	stop_gained	Exon 8 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.460C>T	p.Gln154*	stop_gained	Exon 8 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*585C>T		3_prime_UTR_variant	Exon 9 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*540C>T		3_prime_UTR_variant	Exon 8 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with pseudohypoparathyroidism type Ia (PMID: 23884777). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln227*) in the GNAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNAS are known to be pathogenic (PMID: 11784876, 23281139, 23796510, 25802881). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	49
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.92
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr20-57484595; COSMIC: COSV55675820; COSMIC: COSV55675820;