rs200924357

Positions:

chr20-58853461-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_016592.5(GNAS):c.*42+12575G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,612,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

GNAS
NM_016592.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:3O:1

Conservation

PhyloP100: 1.19

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 -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0046685934).

BP6

Variant 20-58853461-G-A is Benign according to our data. Variant chr20-58853461-G-A is described in ClinVar as [Benign]. Clinvar id is 134498.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (206/152302) while in subpopulation AFR AF= 0.00467 (194/41570). AF 95% confidence interval is 0.00413. There are 0 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4 linkuse as main transcript	c.196G>A	p.Glu66Lys	missense_variant	1/13	ENST00000371100.9
GNAS	NM_016592.5 linkuse as main transcript	c.*42+12575G>A		intron_variant		ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9 linkuse as main transcript	c.196G>A	p.Glu66Lys	missense_variant	1/13	5	NM_080425.4		Q5JWF2-1
GNAS	ENST00000371075.7 linkuse as main transcript	c.*42+12575G>A		intron_variant		1	NM_016592.5		O95467-1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000338

AC:

AN:

245572

Hom.:

AF XY:

0.000194

AC XY:

AN XY:

133826

show subpopulations

Gnomad AFR exome

AF:

0.00464

Gnomad AMR exome

AF:

0.000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000156

AC:

228

AN:

1459920

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726228

show subpopulations

Gnomad4 AFR exome

AF:

0.00572

Gnomad4 AMR exome

AF:

0.000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.00135

AC:

206

AN:

152302

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00467

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.00163

ESP6500AA

AF:

0.00290

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000331

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

7.9

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.0

L;.;L

MutationTaster

Benign

1.0

D;D;D;D;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.74

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.23

T;T;T

Sift4G

Uncertain

0.0040

D;T;D

Polyphen

0.027

B;.;.

Vest4

0.18

MVP

0.23

MPC

0.46

ClinPred

0.0044

GERP RS

3.6

Varity_R

0.046

gMVP

0.43

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