20-58891727-A-T

Position:

• chr20-58891727-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000516.7(GNAS):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 (★★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: GNAS NM_000516.7 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

GNAS (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000516.7 (GNAS) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58891727-A-T is Pathogenic according to our data. Variant chr20-58891727-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 419339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.1A>T	p.Met1?	initiator_codon_variant	1/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-3885A>T		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.1A>T	p.Met1?	initiator_codon_variant	1/13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000354359.12	c.1A>T	p.Met1?	initiator_codon_variant	1/13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.1A>T	p.Met1?	initiator_codon_variant	1/12	1		ENSP00000360136.3
GNAS	ENST00000371075.7	c.*43-3885A>T		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-3885A>T		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-3885A>T		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+2374A>T		intron_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+2178A>T		intron_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-3885A>T		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-3885A>T		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-3885A>T		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+2374A>T		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+2819A>T		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+2178A>T		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+2909A>T		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000461152.6	c.*51+938A>T		intron_variant		5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-3885A>T		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2023	For these reasons, this variant has been classified as Pathogenic. 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 GNAS-related conditions (PMID: 21713996). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 419339). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects GNAS function (PMID: 21713996). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2015	The c.1 A>T variant in the GNAS gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.1 A>T substitution alters the initiatorMethionine codon, and the resultant protein would be described as p.Met1? using a question mark tosignify that it is not known if the loss of Met1 means that all protein translation is completely prevented orif an abnormal protein is produced using an alternate Methionine. The c.1 A>T variant was not observedin approximately 6400 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Missense variantsin involving the same residue (M1V, M1R, M1I) have been reported in the Human Gene MutationDatabase in association with Albright Hereditary Osteodystrophy (Stenson et al., 2014), supporting thefunctional importance of this region of the protein. Additionally, functional characterization of a similarsubstitution (M1I) at the initiation codon resulted in a protein that is truncated by 59 amino acids at the Nterminus (Puzhko et al., 2011). We interpret c.1 A>T as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.34	.;T;.;.;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	0.46	D
PROVEAN	Benign	-1.4	N;N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.031	D;D;D;D;T;D
Sift4G	Benign	0.088	T;T;T;T;D;D
Polyphen		0.38, 0.33	.;B;.;B;.;.
Vest4		0.79
MutPred		0.97		Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);Loss of catalytic residue at M1 (P = 0.0217);
MVP		1.0
ClinPred		0.74	D
GERP RS		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;