rs11554273

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000516.7(GNAS):c.601C>A(p.Arg201Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R201C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GNAS
NM_000516.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:3O:1

Conservation

PhyloP100: 4.12

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a binding_site (size 7) in uniprot entity GNAS2_HUMAN there are 6 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 chr20-58909365-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, 0.983

PP5

Variant 20-58909365-C-A is Pathogenic according to our data. Variant chr20-58909365-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 15937.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-58909365-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7 link	c.601C>A	p.Arg201Ser	missense_variant	Exon 8 of 13	ENST00000371085.8	NP_000507.1	P63092-1O95467A0A0S2Z3H8
GNAS	NM_016592.5 link	c.*507C>A		3_prime_UTR_variant	Exon 8 of 13	ENST00000371075.7	NP_057676.1	O95467-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNAS	ENST00000371085.8 link	c.601C>A	p.Arg201Ser	missense_variant	Exon 8 of 13	1	NM_000516.7	ENSP00000360126.3	P63092-1
GNAS	ENST00000676826.2 link	c.2533C>A	p.Arg845Ser	missense_variant	Exon 8 of 13			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.2488C>A	p.Arg830Ser	missense_variant	Exon 7 of 12	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000354359.12 link	c.604C>A	p.Arg202Ser	missense_variant	Exon 8 of 13	1		ENSP00000346328.7	P63092-4
GNAS	ENST00000371095.7 link	c.559C>A	p.Arg187Ser	missense_variant	Exon 7 of 12	1		ENSP00000360136.3	P63092-2
GNAS	ENST00000470512.6 link	c.427C>A	p.Arg143Ser	missense_variant	Exon 8 of 13	5		ENSP00000499552.2	A0A590UJQ9
GNAS	ENST00000480232.6 link	c.427C>A	p.Arg143Ser	missense_variant	Exon 9 of 14	5		ENSP00000499545.2	A0A590UJQ9
GNAS	ENST00000663479.2 link	c.427C>A	p.Arg143Ser	missense_variant	Exon 8 of 13			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 7 of 12	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 8 of 13	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000478585.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 7 of 12	2		ENSP00000499762.2	A0A590UK28
GNAS	ENST00000481039.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 7 of 12	5		ENSP00000499767.2	A0A590UK28
GNAS	ENST00000485673.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 7 of 12	5		ENSP00000499334.2	A0A590UK28
GNAS	ENST00000488546.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 7 of 12	5		ENSP00000499332.2	A0A590UK28
GNAS	ENST00000492907.6 link	c.382C>A	p.Arg128Ser	missense_variant	Exon 7 of 12	3		ENSP00000499443.2	A0A590UK28
GNAS	ENST00000371075.7 link	c.*507C>A		3_prime_UTR_variant	Exon 8 of 13	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000453292.7 link	c.*462C>A		3_prime_UTR_variant	Exon 7 of 12	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152140

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461402

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ACTH-independent macronodular adrenal hyperplasia 1

Pathogenic:1

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PITUITARY TUMOR 3, GROWTH HORMONE-SECRETING, SOMATIC

Pathogenic:1

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Polyostotic fibrous dysplasia, somatic, mosaic

Pathogenic:1

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

McCune-Albright syndrome

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.;D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.2

.;.;.;.;H;.;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.3

D;D;.;D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;D;.;D

Vest4

0.93

MutPred

0.89

Gain of sheet (P = 0.0827);.;.;.;.;.;.;

MVP

1.0

MPC

3.3

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over