rs797045046

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000516.7(GNAS):c.34C>G(p.Gln12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000898 in 1,113,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

GNAS
NM_000516.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.79

Publications

6 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=0.2930197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7 link	c.34C>G	p.Gln12Glu	missense_variant	Exon 1 of 13	ENST00000371085.8	NP_000507.1	P63092-1O95467A0A0S2Z3H8
GNAS	NM_016592.5 link	c.*43-3852C>G		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1	O95467-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNAS	ENST00000371085.8 link	c.34C>G	p.Gln12Glu	missense_variant	Exon 1 of 13	1	NM_000516.7	ENSP00000360126.3	P63092-1
GNAS	ENST00000354359.12 link	c.34C>G	p.Gln12Glu	missense_variant	Exon 1 of 13	1		ENSP00000346328.7	P63092-4
GNAS	ENST00000371095.7 link	c.34C>G	p.Gln12Glu	missense_variant	Exon 1 of 12	1		ENSP00000360136.3	P63092-2
GNAS	ENST00000371075.7 link	c.*43-3852C>G		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000676826.2 link	c.2069-3852C>G		intron_variant	Intron 1 of 12			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.2069-3852C>G		intron_variant	Intron 1 of 11	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000470512.6 link	c.-39+2407C>G		intron_variant	Intron 1 of 12	5		ENSP00000499552.2	A0A590UJQ9
GNAS	ENST00000480232.6 link	c.-39+2211C>G		intron_variant	Intron 2 of 13	5		ENSP00000499545.2	A0A590UJQ9
GNAS	ENST00000663479.2 link	c.-38-3852C>G		intron_variant	Intron 1 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.-38-3852C>G		intron_variant	Intron 1 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.-38-3852C>G		intron_variant	Intron 2 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000478585.6 link	c.-39+2407C>G		intron_variant	Intron 1 of 11	2		ENSP00000499762.2	A0A590UK28
GNAS	ENST00000481039.6 link	c.-39+2852C>G		intron_variant	Intron 1 of 11	5		ENSP00000499767.2	A0A590UK28
GNAS	ENST00000485673.6 link	c.-39+2211C>G		intron_variant	Intron 1 of 11	5		ENSP00000499334.2	A0A590UK28
GNAS	ENST00000488546.6 link	c.-39+2942C>G		intron_variant	Intron 1 of 11	5		ENSP00000499332.2	A0A590UK28
GNAS	ENST00000461152.6 link	c.*51+971C>G		intron_variant	Intron 1 of 2	5		ENSP00000499274.1	A0A590UJ46
GNAS	ENST00000453292.7 link	c.*43-3852C>G		intron_variant	Intron 1 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000502

AC:

AN:

199320

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000360

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.98e-7

AC:

AN:

1113852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

551478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21800

American (AMR)

AF:

0.0000328

AC:

AN:

30482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14186

East Asian (EAS)

AF:

0.00

AC:

AN:

9892

South Asian (SAS)

AF:

0.00

AC:

AN:

71204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3438

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

896562

Other (OTH)

AF:

0.00

AC:

AN:

38388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0052

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.24

.;T;.;.;T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-0.23

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

PhyloP100

1.8

PROVEAN

Benign

-0.55

N;N;N;N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.78

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

Sift4G

Benign

0.56

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

Polyphen

0.0

.;B;.;B;.;.;.

Vest4

0.20

MutPred

0.31

Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);Loss of MoRF binding (P = 0.0708);.;

MVP

0.38

ClinPred

0.064

GERP RS

1.9

PromoterAI

0.060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over