rs137854530

chr20-58891727-A-Gchr20-58891727-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000516.7(GNAS):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000996 in 1,004,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GNAS NM_000516.7 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.80

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58891727-A-G is Pathogenic according to our data. Variant chr20-58891727-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58891727-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_000516.7	c.1A>G	p.Met1?	start_lost	1/13	ENST00000371085.8
GNAS	NM_016592.5	c.*43-3885A>G		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2069-3885A>G		intron_variant		ENST00000371100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371085.8	c.1A>G	p.Met1?	start_lost	1/13	1	NM_000516.7
GNAS	ENST00000371075.7	c.*43-3885A>G		intron_variant		1	NM_016592.5
GNAS	ENST00000371100.9	c.2069-3885A>G		intron_variant		5	NM_080425.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 9.96e-7 AC: 1 AN: 1004328 Hom.: 0 Cov.: 32 AF XY: 0.00000206 AC XY: 1 AN XY: 486476

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: 0.0000495

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	Experimental studies have shown that disruption of the initiator codon affects GNAS function (PMID: 21713996). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This sequence change affects the initiator methionine of the GNAS mRNA. The next in-frame methionine is located at codon 60. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with Albright’s hereditary osteodystrophy (PMID: 2109828, 21713996). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15927). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2021	Initiation codon variants (Met1?) in GNAS likely lead to the use of an alternate initiation codon and the loss of the first 59 residues (Patten JL et al., 1990; Puzhko S et al., 2011); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 2109828, 27535533, 31546270) -

Pseudohypoparathyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 17, 1990

- -

Cushing syndrome;C0033806:Pseudohypoparathyroidism;C0033835:Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C4540135:Pituitary adenoma 3, multiple types Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Uncertain	23
Dann	Benign	0.95
Eigen	Benign	0.10
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PROVEAN	Benign	-2.0	N;N;N;N;D;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.99, 0.99	.;D;.;D;.;.
Vest4		0.76
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);
MVP		1.0
ClinPred		0.95	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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: rs137854530; hg19: chr20-57466782;