20-58854572-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000676826.2(GNAS):c.1307C>A(p.Ala436Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,534,760 control chromosomes in the GnomAD database, including 1,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A436null) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.073 ( 820 hom., cov: 32)

Exomes 𝑓: 0.027 ( 1015 hom. )

Consequence

GNAS
ENST00000676826.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -3.04

Publications

30 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001532495).

BP6

Variant 20-58854572-C-A is Benign according to our data. Variant chr20-58854572-C-A is described in ClinVar as [Benign]. Clinvar id is 134479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5 link	c.*42+13686C>A		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.1307C>A	p.Ala436Asp	missense_variant	Exon 1 of 13			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.1307C>A	p.Ala436Asp	missense_variant	Exon 1 of 12	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000371075.7 link	c.*42+13686C>A		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000663479.2 link	c.-39+12697C>A		intron_variant	Intron 1 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.-39+12697C>A		intron_variant	Intron 1 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.-39+10498C>A		intron_variant	Intron 2 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000453292.7 link	c.*42+13686C>A		intron_variant	Intron 1 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.0724

AC:

10852

AN:

149844

Hom.:

812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0540

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.0195

Gnomad SAS

AF:

0.0249

Gnomad FIN

AF:

0.00579

Gnomad MID

AF:

0.0455

Gnomad NFE

AF:

0.0267

Gnomad OTH

AF:

0.0601

GnomAD4 exome

AF:

0.0265

AC:

36724

AN:

1384812

Hom.:

1015

Cov.:

AF XY:

0.0264

AC XY:

18132

AN XY:

686660

show subpopulations

African (AFR)

AF:

0.191

AC:

5569

AN:

29212

American (AMR)

AF:

0.0495

AC:

1894

AN:

38282

Ashkenazi Jewish (ASJ)

AF:

0.00654

AC:

167

AN:

25528

East Asian (EAS)

AF:

0.0189

AC:

688

AN:

36404

South Asian (SAS)

AF:

0.0276

AC:

2231

AN:

80718

European-Finnish (FIN)

AF:

0.0114

AC:

404

AN:

35504

Middle Eastern (MID)

AF:

0.0212

AC:

119

AN:

5626

European-Non Finnish (NFE)

AF:

0.0219

AC:

23580

AN:

1075598

Other (OTH)

AF:

0.0358

AC:

2072

AN:

57940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2157

4315

6472

8630

10787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

894

1788

2682

3576

4470

<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:

0.0727

AC:

10898

AN:

149948

Hom.:

820

Cov.:

AF XY:

0.0697

AC XY:

5114

AN XY:

73338

show subpopulations

African (AFR)

AF:

0.195

AC:

7819

AN:

40176

American (AMR)

AF:

0.0540

AC:

820

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3468

East Asian (EAS)

AF:

0.0196

AC:

AN:

5060

South Asian (SAS)

AF:

0.0251

AC:

120

AN:

4774

European-Finnish (FIN)

AF:

0.00579

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.0524

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0267

AC:

1803

AN:

67496

Other (OTH)

AF:

0.0673

AC:

139

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

403

806

1210

1613

2016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0487

Hom.:

TwinsUK

AF:

0.0318

AC:

118

ALSPAC

AF:

0.0252

AC:

ExAC

AF:

0.00957

AC:

996

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Dec 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.066

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.70

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.26

T;T;T

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

N;.;N

PhyloP100

-3.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.18

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.27

T;T;T

Sift4G

Uncertain

0.033

D;T;D

Polyphen

0.0020

B;.;.

Vest4

0.12

MVP

0.18

MPC

0.62

ClinPred

0.14

GERP RS

-4.3

Varity_R

0.10

gMVP

0.19

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over