rs201332059

Positions:

chr20-58853943-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_080425.4(GNAS):c.678T>G(p.Phe226Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,611,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

GNAS
NM_080425.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: -0.157

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:

GNAS (HGNC:):

GNAS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23330995).

BP6

Variant 20-58853943-T-G is Benign according to our data. Variant chr20-58853943-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134487.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5 linkuse as main transcript	c.*42+13057T>G		intron_variant		ENST00000371075.7	NP_057676.1	O95467-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GNAS	ENST00000676826.2 linkuse as main transcript	c.678T>G	p.Phe226Leu	missense_variant	1/13			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 linkuse as main transcript	c.678T>G	p.Phe226Leu	missense_variant	1/12	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000371075.7 linkuse as main transcript	c.*42+13057T>G		intron_variant		1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000663479.2 linkuse as main transcript	c.-39+12068T>G		intron_variant				ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 linkuse as main transcript	c.-39+12068T>G		intron_variant		2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 linkuse as main transcript	c.-39+9869T>G		intron_variant		3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000453292.7 linkuse as main transcript	c.*42+13057T>G		intron_variant		5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

243824

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

133212

show subpopulations

Gnomad AFR exome

AF:

0.0000672

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000225

AC:

328

AN:

1459712

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

163

AN XY:

726094

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000282

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000164

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000266

AC:

ESP6500EA

AF:

0.000488

AC:

ExAC

AF:

0.0000911

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000417

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2018	- -

GNAS-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2024

The GNAS c.678T>G variant is predicted to result in the amino acid substitution p.Phe226Leu. In an alternate transcript (NM_000516.5), this variant is found within a non-coding region (c.-37784T>G). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.021% of alleles in individuals of European (non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.34

T;.;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;.;L

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.74

N;N;N

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.20

T;T;T

Polyphen

0.37

B;.;.

Vest4

0.50

MutPred

0.36

Loss of catalytic residue at F226 (P = 0.0869);Loss of catalytic residue at F226 (P = 0.0869);Loss of catalytic residue at F226 (P = 0.0869);

MVP

0.73

MPC

0.48

ClinPred

0.056

GERP RS

0.27

Varity_R

0.36

gMVP

0.22

Splicing

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