NM_000516.7:c.349G>A

Variant names:

• chr20-58903708-G-A
• rs1555889031
• NM_000516.7:c.349G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000516.7(GNAS):​c.349G>A​(p.Val117Met) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 7.59
• Publications: 0 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 Gene-Disease associations (from GenCC):

• McCune-Albright syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• progressive osseous heteroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudohypoparathyroidism type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudopseudohypoparathyroidism

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• pseudohypoparathyroidism type 1A

  Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 20-58903708-G-A is Pathogenic according to our data. Variant chr20-58903708-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445504.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.349G>A	p.Val117Met	missense_variant	Exon 5 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*255G>A		3_prime_UTR_variant	Exon 5 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.349G>A	p.Val117Met	missense_variant	Exon 5 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2281G>A	p.Val761Met	missense_variant	Exon 5 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2236G>A	p.Val746Met	missense_variant	Exon 4 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.352G>A	p.Val118Met	missense_variant	Exon 5 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.307G>A	p.Val103Met	missense_variant	Exon 4 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.175G>A	p.Val59Met	missense_variant	Exon 5 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.175G>A	p.Val59Met	missense_variant	Exon 6 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.175G>A	p.Val59Met	missense_variant	Exon 5 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.130G>A	p.Val44Met	missense_variant	Exon 4 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.130G>A	p.Val44Met	missense_variant	Exon 5 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.130G>A	p.Val44Met	missense_variant	Exon 4 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.130G>A	p.Val44Met	missense_variant	Exon 4 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.130G>A	p.Val44Met	missense_variant	Exon 4 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.130G>A	p.Val44Met	missense_variant	Exon 4 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.130G>A	p.Val44Met	missense_variant	Exon 4 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*255G>A		3_prime_UTR_variant	Exon 5 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*210G>A		3_prime_UTR_variant	Exon 4 of 12	5		ENSP00000392000.2
GNAS	ENST00000461152.6	c.*305G>A		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Mar 31, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 19, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified as maternally inherited in a patient with musculoskeletal anomaly, but additional clinical information was not included (PMID: 36360262); 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: 36360262) -

Nov 30, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 117 of the GNAS protein (p.Val117Met). This variant has not been reported in the literature in individuals affected with GNAS-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 445504). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;.;D;.;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0080	D;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D;.;D;.
Vest4		0.48
MutPred		0.52		Loss of helix (P = 0.0558);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.3
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.79
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555889031; hg19: chr20-57478763; COSMIC: COSV55675652; COSMIC: COSV55675652;