20-58903752-C-T

Variant names:

• chr20-58903752-C-T
• rs7121
• NM_080425.4:c.2322C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_000516.7(GNAS):​c.393C>T​(p.Ile131Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 1,612,326 control chromosomes in the GnomAD database, including 209,225 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26067 hom., cov: 28)
  • Exomes 𝑓: 0.49 (183158 hom.)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.364
• Publications: 128 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 -17 ACMG points.

• BP6: Variant 20-58903752-C-T is Benign according to our data. Variant chr20-58903752-C-T is described in ClinVar as Benign. ClinVar VariationId is 197681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 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.2322C>T	p.Ile774Ile	synonymous	Exon 5 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_000516.7	MANE Select	c.393C>T	p.Ile131Ile	synonymous	Exon 5 of 13	NP_000507.1	P63092-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*299C>T		3_prime_UTR	Exon 5 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.2322C>T	p.Ile774Ile	synonymous	Exon 5 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.393C>T	p.Ile131Ile	synonymous	Exon 5 of 13	ENSP00000360126.3	P63092-1
	GNAS	ENST00000676826.2		c.2325C>T	p.Ile775Ile	synonymous	Exon 5 of 13	ENSP00000504675.2	A0A7I2V5R6

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86368 AN: 151368 Hom.: 26014 Cov.: 28

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.623

GnomAD2 exomes AF: 0.543 AC: 136663 AN: 251484 AF XY: 0.539

Gnomad AFR exome AF: 0.758

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.631

Gnomad EAS exome AF: 0.649

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.495 AC: 722387 AN: 1460840 Hom.: 183158 Cov.: 38 AF XY: 0.497 AC XY: 361154 AN XY: 726808

African (AFR) AF: 0.768 AC: 25692 AN: 33468

American (AMR) AF: 0.617 AC: 27608 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 16467 AN: 26130

East Asian (EAS) AF: 0.603 AC: 23944 AN: 39694

South Asian (SAS) AF: 0.568 AC: 48968 AN: 86248

European-Finnish (FIN) AF: 0.373 AC: 19910 AN: 53408

Middle Eastern (MID) AF: 0.696 AC: 4015 AN: 5766

European-Non Finnish (NFE) AF: 0.471 AC: 523200 AN: 1111052

Other (OTH) AF: 0.540 AC: 32583 AN: 60352

GnomAD4 genome AF: 0.571 AC: 86486 AN: 151486 Hom.: 26067 Cov.: 28 AF XY: 0.568 AC XY: 42026 AN XY: 74016

African (AFR) AF: 0.751 AC: 30948 AN: 41226

American (AMR) AF: 0.594 AC: 9051 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2180 AN: 3464

East Asian (EAS) AF: 0.649 AC: 3320 AN: 5114

South Asian (SAS) AF: 0.577 AC: 2753 AN: 4774

European-Finnish (FIN) AF: 0.357 AC: 3762 AN: 10524

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.483 AC: 32774 AN: 67852

Other (OTH) AF: 0.627 AC: 1319 AN: 2102

Alfa AF: 0.530 Hom.: 75891

Bravo AF: 0.598

Asia WGS AF: 0.644 AC: 2238 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Progressive osseous heteroplasia (1)
-	-	1	Pseudohypoparathyroidism type 1B (1)
-	-	1	Pseudohypoparathyroidism type 1C (1)
-	-	1	Pseudohypoparathyroidism type I A (1)
-	-	1	Pseudopseudohypoparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.5
DANN	Benign	0.89
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs7121; hg19: chr20-57478807; COSMIC: COSV55672982; COSMIC: COSV55672982;