20-58903792-G-T

Variant names:

• chr20-58903792-G-T
• rs1555889131
• NM_000516.7:c.432+1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000516.7(GNAS):​c.432+1G>T variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNAS NM_000516.7 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.40
• 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 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.101265825 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58903792-G-T is Pathogenic according to our data. Variant chr20-58903792-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1028314.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.432+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*338+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.432+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*338+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2364+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2319+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.435+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.390+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.258+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.258+1G>T		splice_donor_variant, intron_variant	Intron 6 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.258+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 5 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.213+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	3		ENSP00000499443.2
GNAS	ENST00000453292.7	c.*293+1G>T		splice_donor_variant, intron_variant	Intron 4 of 11	5		ENSP00000392000.2
GNAS	ENST00000461152.6	c.*389G>T		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

McCune-Albright syndrome Pathogenic:1

Apr 20, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.4
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -36
DS_DL_spliceai		0.97		Position offset: -1

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

Other links and lift over

dbSNP: rs1555889131; hg19: chr20-57478847;