NM_080425.4:c.1798C>G

Variant names:

• chr20-58855063-C-G
• rs74897360
• NM_080425.4:c.1798C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600C) has been classified as Uncertain significance.

• 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
• Publications: 18 publications found

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-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)

ENSG00000293655 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 134493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 830 AD,Mitochondrial,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.1798C>G	p.Arg600Gly	missense	Exon 1 of 13	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+14177C>G		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.1798C>G	p.Arg600Gly	missense	Exon 1 of 12	NP_001397842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.1798C>G	p.Arg600Gly	missense	Exon 1 of 13	ENSP00000360141.3
	GNAS	ENST00000676826.2		c.1798C>G	p.Arg600Gly	missense	Exon 1 of 13	ENSP00000504675.2
	GNAS	ENST00000371102.8	TSL:5	c.1798C>G	p.Arg600Gly	missense	Exon 1 of 12	ENSP00000360143.4

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

GnomAD2 exomes AF: 0.00632 AC: 1564 AN: 247626 AF XY: 0.00680

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 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

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00168 AC: 75 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0118 AC: 1015 AN: 86258

European-Finnish (FIN) AF: 0.00674 AC: 354 AN: 52514

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.00774 AC: 8610 AN: 1111854

Other (OTH) AF: 0.00547 AC: 330 AN: 60360

GnomAD4 genome AF: 0.00545 AC: 830 AN: 152376 Hom.: 4 Cov.: 33 AF XY: 0.00557 AC XY: 415 AN XY: 74510

African (AFR) AF: 0.00180 AC: 75 AN: 41596

American (AMR) AF: 0.00320 AC: 49 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4830

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00783 AC: 533 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

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

Aug 31, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GNAS: BP4, BS1, BS2

Nov 14, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32428920)

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2 Other:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: 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

Nov 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.23
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.19
Sift	Benign	0.77	T
Sift4G	Benign	0.51	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
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

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