rs11554273

Positions:

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. R201G) 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:

Genome browser will be placed here

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 13 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 ClinVar as [Pathogenic]. Clinvar id is 15933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, GNAS

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/exons	MANE
GNAS	NM_080425.4 linkuse as main transcript	c.2530C>A	p.Arg844Ser	missense_variant	8/13	ENST00000371100.9
GNAS	NM_000516.7 linkuse as main transcript	c.601C>A	p.Arg201Ser	missense_variant	8/13	ENST00000371085.8
GNAS	NM_016592.5 linkuse as main transcript	c.*507C>A		3_prime_UTR_variant	8/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
GNAS	ENST00000371100.9 linkuse as main transcript	c.2530C>A	p.Arg844Ser	missense_variant	8/13	5	NM_080425.4	Q5JWF2-1
GNAS	ENST00000371085.8 linkuse as main transcript	c.601C>A	p.Arg201Ser	missense_variant	8/13	1	NM_000516.7	P63092-1
GNAS	ENST00000371075.7 linkuse as main transcript	c.*507C>A		3_prime_UTR_variant	8/13	1	NM_016592.5	O95467-1

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2003

- -

PITUITARY TUMOR 3, GROWTH HORMONE-SECRETING, SOMATIC

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2003

- -

Polyostotic fibrous dysplasia, somatic, mosaic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2003

- -

McCune-Albright syndrome

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

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

MutationTaster

Benign

1.0

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

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