rs3730168

Variant names:

• chr20-58903884-G-A
• rs3730168
• NM_080425.4:c.2361+93G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000516.7(GNAS):​c.432+93G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,361,808 control chromosomes in the GnomAD database, including 75,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9821 hom., cov: 32)
  • Exomes 𝑓: 0.33 (65522 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.788
• Publications: 18 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):

• progressive osseous heteroplasia

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

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

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

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

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

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-58903884-G-A is Benign according to our data. Variant chr20-58903884-G-A is described in ClinVar as Benign. ClinVar VariationId is 1238617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 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.2361+93G>A		intron	N/A	NP_536350.2
	GNAS	NM_000516.7	MANE Select	c.432+93G>A		intron	N/A	NP_000507.1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*338+93G>A		intron	N/A	NP_057676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2361+93G>A		intron	N/A	ENSP00000360141.3
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.432+93G>A		intron	N/A	ENSP00000360126.3
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*338+93G>A		intron	N/A	ENSP00000360115.3

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53636 AN: 151976 Hom.: 9803 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.325 AC: 393706 AN: 1209714 Hom.: 65522 AF XY: 0.326 AC XY: 200045 AN XY: 613274

African (AFR) AF: 0.461 AC: 13070 AN: 28356

American (AMR) AF: 0.306 AC: 13590 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 7841 AN: 24458

East Asian (EAS) AF: 0.287 AC: 11072 AN: 38548

South Asian (SAS) AF: 0.347 AC: 28002 AN: 80650

European-Finnish (FIN) AF: 0.290 AC: 15376 AN: 53078

Middle Eastern (MID) AF: 0.321 AC: 1360 AN: 4242

European-Non Finnish (NFE) AF: 0.324 AC: 286253 AN: 884140

Other (OTH) AF: 0.330 AC: 17142 AN: 51876

GnomAD4 genome AF: 0.353 AC: 53689 AN: 152094 Hom.: 9821 Cov.: 32 AF XY: 0.350 AC XY: 26032 AN XY: 74340

African (AFR) AF: 0.454 AC: 18838 AN: 41474

American (AMR) AF: 0.324 AC: 4952 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3472

East Asian (EAS) AF: 0.266 AC: 1376 AN: 5166

South Asian (SAS) AF: 0.324 AC: 1562 AN: 4814

European-Finnish (FIN) AF: 0.292 AC: 3092 AN: 10576

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21652 AN: 67982

Other (OTH) AF: 0.336 AC: 711 AN: 2116

Alfa AF: 0.323 Hom.: 14711

Bravo AF: 0.358

Asia WGS AF: 0.282 AC: 979 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.22
DANN	Benign	0.35
PhyloP100		-0.79
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: rs3730168; hg19: chr20-57478939; COSMIC: COSV55673083; COSMIC: COSV55673083;