rs137854537

Variant names:

• chr20-58910740-G-A
• rs137854537
• NM_000516.7:c.1096G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58910740-G-A
• chr20-58910740-G-C
• chr20-58910740-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000516.7(GNAS):​c.1096G>A​(p.Ala366Thr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A366S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 9.52
• Publications: 27 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr20-58910740-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 15944.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 20-58910740-G-A is Pathogenic according to our data. Variant chr20-58910740-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 501069.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.1096G>A	p.Ala366Thr	missense_variant	Exon 13 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*1002G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.1096G>A	p.Ala366Thr	missense_variant	Exon 13 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.3028G>A	p.Ala1010Thr	missense_variant	Exon 13 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2983G>A	p.Ala995Thr	missense_variant	Exon 12 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.1099G>A	p.Ala367Thr	missense_variant	Exon 13 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.1054G>A	p.Ala352Thr	missense_variant	Exon 12 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.922G>A	p.Ala308Thr	missense_variant	Exon 13 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.922G>A	p.Ala308Thr	missense_variant	Exon 14 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.922G>A	p.Ala308Thr	missense_variant	Exon 13 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 12 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 13 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 12 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 12 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 12 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 12 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.877G>A	p.Ala293Thr	missense_variant	Exon 12 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*1002G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*957G>A		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 366 of the GNAS protein (p.Ala366Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GNAS-related conditions (PMID: 21525160, 23884777, 29379892, 29970488, 31886927). In at least one individual the variant was observed to be de novo. This variant is also known as p.Ala367Thr. ClinVar contains an entry for this variant (Variation ID: 501069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNAS protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GNAS: PM2, PP1, PP2, PP3, PS4:Supporting -

Pseudohypoparathyroidism type I A Pathogenic:1

Nov 18, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2 moderated, PM6 moderated, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;D;.;.;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	.;.;.;H;.;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D;.
Vest4		0.91
MutPred		0.82		Gain of helix (P = 0.0199);.;.;.;.;.;.;
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing

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: rs137854537; hg19: chr20-57485795; COSMIC: COSV55686790; COSMIC: COSV55686790;