rs6026593

Variant names:

• chr20-58904078-A-G
• rs6026593
• NM_000516.7:c.432+287A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000516.7(GNAS):​c.432+287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,182 control chromosomes in the GnomAD database, including 3,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3896 hom., cov: 32)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.118
• Publications: 11 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-58904078-A-G is Benign according to our data. Variant chr20-58904078-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236136.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.432+287A>G		intron_variant	Intron 5 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*338+287A>G		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+287A>G		intron_variant	Intron 5 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*338+287A>G		intron_variant	Intron 5 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2364+287A>G		intron_variant	Intron 5 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2319+287A>G		intron_variant	Intron 4 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.435+287A>G		intron_variant	Intron 5 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.390+287A>G		intron_variant	Intron 4 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.258+287A>G		intron_variant	Intron 5 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.258+287A>G		intron_variant	Intron 6 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.258+287A>G		intron_variant	Intron 5 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.213+287A>G		intron_variant	Intron 4 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.213+287A>G		intron_variant	Intron 5 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.213+287A>G		intron_variant	Intron 4 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.213+287A>G		intron_variant	Intron 4 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.213+287A>G		intron_variant	Intron 4 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.213+287A>G		intron_variant	Intron 4 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.213+287A>G		intron_variant	Intron 4 of 11	3		ENSP00000499443.2
GNAS	ENST00000453292.7	c.*293+287A>G		intron_variant	Intron 4 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28465 AN: 152064 Hom.: 3877 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.188 AC: 28542 AN: 152182 Hom.: 3896 Cov.: 32 AF XY: 0.184 AC XY: 13677 AN XY: 74408

African (AFR) AF: 0.388 AC: 16091 AN: 41480

American (AMR) AF: 0.139 AC: 2132 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3472

East Asian (EAS) AF: 0.134 AC: 692 AN: 5182

South Asian (SAS) AF: 0.106 AC: 514 AN: 4828

European-Finnish (FIN) AF: 0.0951 AC: 1008 AN: 10594

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7247 AN: 68006

Other (OTH) AF: 0.191 AC: 404 AN: 2110

Alfa AF: 0.137 Hom.: 6273

Bravo AF: 0.199

Asia WGS AF: 0.192 AC: 665 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.79
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs6026593; hg19: chr20-57479133;