rs74897360

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016592.5(GNAS):c.*42+14177C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 1,613,168 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 61 hom. )

Consequence

GNAS
NM_016592.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.235

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=0.0050272048).

BP6

Variant 20-58855063-C-G is Benign according to our data. Variant chr20-58855063-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 134493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58855063-C-G is described in Lovd as [Benign]. Variant chr20-58855063-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00545 (830/152376) while in subpopulation SAS AF= 0.0116 (56/4830). AF 95% confidence interval is 0.00917. There are 4 homozygotes in gnomad4. There are 415 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 SM,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_080425.4 linkuse as main transcript	c.1798C>G	p.Arg600Gly	missense_variant	1/13	ENST00000371100.9	NP_536350.2
GNAS	NM_016592.5 linkuse as main transcript	c.*42+14177C>G		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371100.9 linkuse as main transcript	c.1798C>G	p.Arg600Gly	missense_variant	1/13	5	NM_080425.4	ENSP00000360141		Q5JWF2-1
GNAS	ENST00000371075.7 linkuse as main transcript	c.*42+14177C>G		intron_variant		1	NM_016592.5	ENSP00000360115		O95467-1

Frequencies

GnomAD3 genomes

AF:

0.00545

AC:

830

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00320

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00785

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00632

AC:

1564

AN:

247626

Hom.:

AF XY:

0.00680

AC XY:

917

AN XY:

134948

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0113

Gnomad FIN exome

AF:

0.00706

Gnomad NFE exome

AF:

0.00858

Gnomad OTH exome

AF:

0.00399

GnomAD4 exome

AF:

0.00717

AC:

10481

AN:

1460792

Hom.:

Cov.:

AF XY:

0.00727

AC XY:

5284

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00674

Gnomad4 NFE exome

AF:

0.00774

Gnomad4 OTH exome

AF:

0.00547

GnomAD4 genome

AF:

0.00545

AC:

830

AN:

152376

Hom.:

Cov.:

AF XY:

0.00557

AC XY:

415

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.00783

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00591

Hom.:

Bravo

AF:

0.00440

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00151

AC:

ESP6500EA

AF:

0.00565

AC:

ExAC

AF:

0.00675

AC:

816

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GNAS: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2020	This variant is associated with the following publications: (PMID: 32428920) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Nov 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.31

T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.61

T;T;T

MetaRNN

Benign

0.0050

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.2

L;.;L

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.77

T;T;T

Sift4G

Benign

0.51

T;T;T

Polyphen

0.0060

B;.;.

Vest4

0.27

MVP

0.12

MPC

0.53

ClinPred

0.0074

GERP RS

1.8

Varity_R

0.082

gMVP

0.39

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