NM_000516.7:c.531-562T>C

Variant names:

• chr20-58908600-T-C
• rs234630
• NM_000516.7:c.531-562T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000516.7(GNAS):​c.531-562T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 151,972 control chromosomes in the GnomAD database, including 4,765 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4765 hom., cov: 32)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.531-562T>C		intron_variant	Intron 6 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*437-562T>C		intron_variant	Intron 6 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.531-562T>C		intron_variant	Intron 6 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*437-562T>C		intron_variant	Intron 6 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2463-562T>C		intron_variant	Intron 6 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2418-562T>C		intron_variant	Intron 5 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.534-562T>C		intron_variant	Intron 6 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.489-562T>C		intron_variant	Intron 5 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.357-562T>C		intron_variant	Intron 6 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.357-562T>C		intron_variant	Intron 7 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.357-562T>C		intron_variant	Intron 6 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.312-562T>C		intron_variant	Intron 5 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.312-562T>C		intron_variant	Intron 6 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.312-562T>C		intron_variant	Intron 5 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.312-562T>C		intron_variant	Intron 5 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.312-562T>C		intron_variant	Intron 5 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.312-562T>C		intron_variant	Intron 5 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.312-562T>C		intron_variant	Intron 5 of 11	3		ENSP00000499443.2
GNAS	ENST00000453292.7	c.*392-562T>C		intron_variant	Intron 5 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34747 AN: 151854 Hom.: 4761 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.229 AC: 34744 AN: 151972 Hom.: 4765 Cov.: 32 AF XY: 0.228 AC XY: 16900 AN XY: 74244

African (AFR) AF: 0.0743 AC: 3079 AN: 41466

American (AMR) AF: 0.272 AC: 4147 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1317 AN: 3468

East Asian (EAS) AF: 0.145 AC: 749 AN: 5182

South Asian (SAS) AF: 0.270 AC: 1298 AN: 4812

European-Finnish (FIN) AF: 0.251 AC: 2634 AN: 10502

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20603 AN: 67974

Other (OTH) AF: 0.246 AC: 517 AN: 2104

Alfa AF: 0.284 Hom.: 7324

Bravo AF: 0.222

Asia WGS AF: 0.198 AC: 688 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.090
DANN	Benign	0.28
PhyloP100		-2.3
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: rs234630; hg19: chr20-57483655;