20-58898945-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_080425.4(GNAS):c.2146G>T(p.Gly716Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G716S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GNAS
NM_080425.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

McCune-Albright syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
progressive osseous heteroplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohypoparathyroidism type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudohypoparathyroidism type 1C
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
pseudopseudohypoparathyroidism
Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
pseudohypoparathyroidism type 1A
Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

GNAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38053524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GNAS	NM_080425.4 link	c.2146G>T	p.Gly716Cys	missense_variant	Exon 3 of 13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7 link	c.217G>T	p.Gly73Cys	missense_variant	Exon 3 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5 link	c.*120G>T		3_prime_UTR_variant	Exon 3 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GNAS	ENST00000371100.9 link	c.2146G>T	p.Gly716Cys	missense_variant	Exon 3 of 13	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8 link	c.217G>T	p.Gly73Cys	missense_variant	Exon 3 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2 link	c.2146G>T	p.Gly716Cys	missense_variant	Exon 3 of 13			ENSP00000504675.2
GNAS	ENST00000354359.12 link	c.217G>T	p.Gly73Cys	missense_variant	Exon 3 of 13	1		ENSP00000346328.7
GNAS	ENST00000470512.6 link	c.40G>T	p.Gly14Cys	missense_variant	Exon 3 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.40G>T	p.Gly14Cys	missense_variant	Exon 4 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.40G>T	p.Gly14Cys	missense_variant	Exon 3 of 13			ENSP00000499353.2
GNAS	ENST00000371075.7 link	c.*120G>T		3_prime_UTR_variant	Exon 3 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000371102.8 link	c.2141+3261G>T		intron_variant	Intron 2 of 11	5		ENSP00000360143.4
GNAS	ENST00000371095.7 link	c.212+3261G>T		intron_variant	Intron 2 of 11	1		ENSP00000360136.3
GNAS	ENST00000462499.6 link	c.35+3261G>T		intron_variant	Intron 2 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.35+3261G>T		intron_variant	Intron 3 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.35+3261G>T		intron_variant	Intron 2 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.35+3261G>T		intron_variant	Intron 2 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.35+3261G>T		intron_variant	Intron 2 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.35+3261G>T		intron_variant	Intron 2 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6 link	c.35+3261G>T		intron_variant	Intron 2 of 11	3		ENSP00000499443.2
GNAS	ENST00000461152.6 link	c.*124+3261G>T		intron_variant	Intron 2 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7 link	c.*115+3261G>T		intron_variant	Intron 2 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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:

6.84e-7

AC:

AN:

1461400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727070

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111568

Other (OTH)

AF:

0.00

AC:

AN:

60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GNAS protein function. This variant has not been reported in the literature in individuals affected with GNAS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 73 of the GNAS protein (p.Gly73Cys).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;D;.;T;T

Eigen

Benign

0.057

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.71

T;D;D;D;D;T;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.38

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

0.0

.;.;.;N;N;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.9

N;N;.;N;N;D;.

REVEL

Uncertain

0.54

Sift

Benign

0.072

T;T;.;T;D;D;.

Sift4G

Benign

0.066

T;T;D;T;T;T;D

Vest4

0.76

ClinPred

0.96

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.74

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over