rs74897360

Positions:

• chr20-58855063-C-G
• chr20-58855063-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080425.4(GNAS):​c.1798C>G​(p.Arg600Gly) variant causes a missense 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. 14/19 in silico tools predict 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_080425.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.235

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 (HGNC:):

ACMG classification

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_016592.5	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	ENST00000676826.2	c.1798C>G	p.Arg600Gly	missense_variant	1/13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.1798C>G	p.Arg600Gly	missense_variant	1/12	5		ENSP00000360143.4
GNAS	ENST00000371075.7	c.*42+14177C>G		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000663479.2	c.-39+13188C>G		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.-39+13188C>G		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-39+10989C>G		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000453292.7	c.*42+14177C>G		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 830 AN: 152258 Hom.: 4 Cov.: 33

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.: 12 AF XY: 0.00680 AC XY: 917 AN XY: 134948

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.: 61 Cov.: 34 AF XY: 0.00727 AC XY: 5284 AN XY: 726710

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.: 4 Cov.: 33 AF XY: 0.00557 AC XY: 415 AN XY: 74510

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.: 6

Bravo AF: 0.00440

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00151 AC: 6

ESP6500EA AF: 0.00565 AC: 47

ExAC AF: 0.00675 AC: 816

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00703

EpiControl AF: 0.00634

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GNAS: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 31, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2020	This variant is associated with the following publications: (PMID: 32428920) -

not specified Benign:2 Other: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	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs74897360; hg19: chr20-57430118; COSMIC: COSV58332610; COSMIC: COSV58332610;