chr20-58854253-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000676826.2(GNAS):c.988A>G(p.Ile330Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,613,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I330I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

GNAS
ENST00000676826.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.146

Publications

8 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 links:

GNAS-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

GNAS-AS1 Gene-Disease associations (from GenCC):

pseudohypoparathyroidism type 1B
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GNAS-AS1 links:

ENSG00000293655 (HGNC:):

ENSG00000293655 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06338331).

BP6

Variant 20-58854253-A-G is Benign according to our data. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492. Variant chr20-58854253-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134492.

BS2

High AC in GnomAd4 at 6 AD,Mitochondrial,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5 link	c.*42+13367A>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	ENST00000676826.2 link	c.988A>G	p.Ile330Val	missense_variant	Exon 1 of 13			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.988A>G	p.Ile330Val	missense_variant	Exon 1 of 12	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000371075.7 link	c.*42+13367A>G		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000663479.2 link	c.-39+12378A>G		intron_variant	Intron 1 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.-39+12378A>G		intron_variant	Intron 1 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.-39+10179A>G		intron_variant	Intron 2 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000453292.7 link	c.*42+13367A>G		intron_variant	Intron 1 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152148

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:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000770

AC:

AN:

246786

AF XY:

0.0000892

show subpopulations

Gnomad AFR exome

AF:

0.0000662

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000359

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1460926

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.000277

AC:

AN:

39694

South Asian (SAS)

AF:

0.000325

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111768

Other (OTH)

AF:

0.00

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000662

AC:

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:1

Jul 30, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GNAS-related disorder

Uncertain:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The GNAS c.988A>G variant is predicted to result in the amino acid substitution p.Ile330Val. Of note, in the more commonly reported transcript (NM_000516.5) this variant is pre-coding (c.-37474A>G). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD. 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. -

Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types

Benign:1

May 09, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.62

T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.90

L;.;L

PhyloP100

0.15

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.070

N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0040

D;D;D

Sift4G

Benign

0.27

T;T;T

Polyphen

0.010

B;.;.

Vest4

0.15

MVP

0.55

MPC

0.34

ClinPred

0.076

GERP RS

2.6

Varity_R

0.096

gMVP

0.096

Mutation Taster

=89/11

polymorphism

(source)

Splicing

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