20-58905443-C-T

Variant names:

• chr20-58905443-C-T
• rs137854532
• NM_000516.7:c.493C>T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000516.7(GNAS):​c.493C>T​(p.Arg165Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 5.16

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a helix (size 4) in uniprot entity GNAS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58905444-G-A is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the GNAS gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 64 curated benign missense variants. Gene score misZ: 2.6546 (below the threshold of 3.09). Trascript score misZ: 4.8361 (above the threshold of 3.09). GenCC associations: The gene is linked to ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 20-58905443-C-T is Pathogenic according to our data. Variant chr20-58905443-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58905443-C-T is described in Lovd as [Pathogenic]. Variant chr20-58905443-C-T is described in Lovd as [Likely_pathogenic]. Variant chr20-58905443-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.493C>T	p.Arg165Cys	missense_variant	Exon 6 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*399C>T		3_prime_UTR_variant	Exon 6 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.493C>T	p.Arg165Cys	missense_variant	Exon 6 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2425C>T	p.Arg809Cys	missense_variant	Exon 6 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2380C>T	p.Arg794Cys	missense_variant	Exon 5 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.496C>T	p.Arg166Cys	missense_variant	Exon 6 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.451C>T	p.Arg151Cys	missense_variant	Exon 5 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.319C>T	p.Arg107Cys	missense_variant	Exon 6 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.319C>T	p.Arg107Cys	missense_variant	Exon 7 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.319C>T	p.Arg107Cys	missense_variant	Exon 6 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 5 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 6 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 5 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 5 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 5 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 5 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.274C>T	p.Arg92Cys	missense_variant	Exon 5 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*399C>T		3_prime_UTR_variant	Exon 6 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*354C>T		3_prime_UTR_variant	Exon 5 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455850 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 165 of the GNAS protein (p.Arg165Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNAS-related conditions (PMID: 8388883, 23281139, 25802881). In at least one individual the variant was observed to be de novo. This variant is also known as c.496C>T p.(Arg166Cys). ClinVar contains an entry for this variant (Variation ID: 15932). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this missense change alters GNAS gene expression (PMID: 8388883). For these reasons, this variant has been classified as Pathogenic. -

Sep 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8388883, 34008892, 26336083, 9506735, 28497657, 31886927, 29072892, 25802881, 27542269, 16789628) -

Pseudohypoparathyroidism Pathogenic:1 Other:1

Sep 30, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Pseudohypoparathyroidism type I A Pathogenic:1

Dec 06, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 4 Pathogenic:1

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP2, PP3, PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;D;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.9	.;.;.;.;.;H;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.5	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;.;D;.
Vest4		0.91
MutPred		0.73		Loss of sheet (P = 7e-04);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		3.7
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854532; hg19: chr20-57480498; COSMIC: COSV55688292; COSMIC: COSV55688292;