NM_000516.7:c.555C>T

Variant names:

• chr20-58909186-C-T
• rs8620
• NM_080425.4:c.2484C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000516.7(GNAS):​c.555C>T​(p.Ile185Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,874 control chromosomes in the GnomAD database, including 2,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1313 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1308 hom.)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.27
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• progressive osseous heteroplasia

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

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

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

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

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 20-58909186-C-T is Benign according to our data. Variant chr20-58909186-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000516.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2484C>T	p.Ile828Ile	synonymous	Exon 7 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_000516.7	MANE Select	c.555C>T	p.Ile185Ile	synonymous	Exon 7 of 13	NP_000507.1	P63092-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*461C>T		3_prime_UTR	Exon 7 of 13	NP_057676.1	O95467-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2484C>T	p.Ile828Ile	synonymous	Exon 7 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.555C>T	p.Ile185Ile	synonymous	Exon 7 of 13	ENSP00000360126.3	P63092-1
	GNAS	ENST00000676826.2		c.2487C>T	p.Ile829Ile	synonymous	Exon 7 of 13	ENSP00000504675.2	A0A7I2V5R6

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11885 AN: 152072 Hom.: 1310 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0277 AC: 6968 AN: 251482 AF XY: 0.0232

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0185 AC: 26974 AN: 1461684 Hom.: 1308 Cov.: 31 AF XY: 0.0176 AC XY: 12792 AN XY: 727134

African (AFR) AF: 0.260 AC: 8700 AN: 33456

American (AMR) AF: 0.0198 AC: 885 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 555 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0110 AC: 946 AN: 86246

European-Finnish (FIN) AF: 0.00300 AC: 160 AN: 53420

Middle Eastern (MID) AF: 0.0395 AC: 228 AN: 5766

European-Non Finnish (NFE) AF: 0.0125 AC: 13891 AN: 1111854

Other (OTH) AF: 0.0266 AC: 1605 AN: 60382

GnomAD4 genome AF: 0.0783 AC: 11909 AN: 152190 Hom.: 1313 Cov.: 32 AF XY: 0.0755 AC XY: 5623 AN XY: 74432

African (AFR) AF: 0.246 AC: 10195 AN: 41456

American (AMR) AF: 0.0324 AC: 496 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4830

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 909 AN: 68014

Other (OTH) AF: 0.0563 AC: 119 AN: 2114

Alfa AF: 0.0312 Hom.: 868

Bravo AF: 0.0875

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0166

EpiControl AF: 0.0160

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs8620; hg19: chr20-57484241; COSMIC: COSV99671336;