chr20-58854641-C-G

Position:

chr20-58854641-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016592.5(GNAS):c.*42+13755C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,505,282 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 4 hom., cov: 33)

Exomes 𝑓: 0.015 ( 6 hom. )

Consequence

GNAS
NM_016592.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.480

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024326742).

BP6

Variant 20-58854641-C-G is Benign according to our data. Variant chr20-58854641-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 134480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58854641-C-G is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4 linkuse as main transcript	c.1376C>G	p.Pro459Arg	missense_variant	1/13	ENST00000371100.9
GNAS	NM_016592.5 linkuse as main transcript	c.*42+13755C>G		intron_variant		ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9 linkuse as main transcript	c.1376C>G	p.Pro459Arg	missense_variant	1/13	5	NM_080425.4		Q5JWF2-1
GNAS	ENST00000371075.7 linkuse as main transcript	c.*42+13755C>G		intron_variant		1	NM_016592.5		O95467-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1577

AN:

149672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00409

Gnomad SAS

AF:

0.00795

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.00383

Gnomad OTH

AF:

0.00920

GnomAD3 exomes

AF:

0.00947

AC:

1187

AN:

125312

Hom.:

AF XY:

0.00972

AC XY:

669

AN XY:

68834

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.00230

Gnomad EAS exome

AF:

0.00303

Gnomad SAS exome

AF:

0.0133

Gnomad FIN exome

AF:

0.00351

Gnomad NFE exome

AF:

0.00662

Gnomad OTH exome

AF:

0.00889

GnomAD4 exome

AF:

0.0148

AC:

20063

AN:

1355510

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

9580

AN XY:

669260

show subpopulations

Gnomad4 AFR exome

AF:

0.0885

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00175

Gnomad4 SAS exome

AF:

0.0111

Gnomad4 FIN exome

AF:

0.000650

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0106

AC:

1586

AN:

149772

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

759

AN XY:

73294

show subpopulations

Gnomad4 AFR

AF:

0.0286

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00410

Gnomad4 SAS

AF:

0.00796

Gnomad4 FIN

AF:

0.000755

Gnomad4 NFE

AF:

0.00383

Gnomad4 OTH

AF:

0.00960

Alfa

AF:

0.0356

Hom.:

ExAC

AF:

0.00410

AC:

325

ClinVar

Significance: Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2018	This variant is associated with the following publications: (PMID: 30022773) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

GNAS-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.29

CADD

Benign

8.4

DANN

Benign

0.97

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.085

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

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

PROVEAN

Benign

-0.46

REVEL

Benign

0.024

Sift

Benign

0.10

Sift4G

Benign

0.50

Vest4

0.097

MVP

0.21

ClinPred

0.0055

GERP RS

0.082

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