20-58905365-T-C

Variant names:

• chr20-58905365-T-C
• rs3730170
• NM_080425.4:c.2362-18T>C

Variant summary

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

The NM_080425.4(GNAS):​c.2362-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,427,932 control chromosomes in the GnomAD database, including 1,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (678 hom., cov: 32)
  • Exomes 𝑓: 0.026 (973 hom.)
• Consequence: GNAS NM_080425.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.730
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-58905365-T-C is Benign according to our data. Variant chr20-58905365-T-C is described in ClinVar as Benign. ClinVar VariationId is 198088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2362-18T>C		intron	N/A	NP_536350.2
	GNAS	NM_000516.7	MANE Select	c.433-18T>C		intron	N/A	NP_000507.1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*339-18T>C		intron	N/A	NP_057676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2362-18T>C		intron	N/A	ENSP00000360141.3
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.433-18T>C		intron	N/A	ENSP00000360126.3
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*339-18T>C		intron	N/A	ENSP00000360115.3

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10229 AN: 152124 Hom.: 676 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0597

GnomAD2 exomes AF: 0.0345 AC: 8665 AN: 251376 AF XY: 0.0314

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0318

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.0356

Gnomad FIN exome AF: 0.0208

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0384

GnomAD4 exome AF: 0.0262 AC: 33465 AN: 1275690 Hom.: 973 Cov.: 20 AF XY: 0.0257 AC XY: 16570 AN XY: 644162

African (AFR) AF: 0.185 AC: 5528 AN: 29868

American (AMR) AF: 0.0338 AC: 1504 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 670 AN: 24992

East Asian (EAS) AF: 0.0502 AC: 1952 AN: 38846

South Asian (SAS) AF: 0.0173 AC: 1427 AN: 82652

European-Finnish (FIN) AF: 0.0196 AC: 1045 AN: 53296

Middle Eastern (MID) AF: 0.0934 AC: 506 AN: 5416

European-Non Finnish (NFE) AF: 0.0198 AC: 18684 AN: 942032

Other (OTH) AF: 0.0397 AC: 2149 AN: 54094

GnomAD4 genome AF: 0.0673 AC: 10248 AN: 152242 Hom.: 678 Cov.: 32 AF XY: 0.0656 AC XY: 4884 AN XY: 74468

African (AFR) AF: 0.175 AC: 7263 AN: 41506

American (AMR) AF: 0.0489 AC: 749 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3468

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5184

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4820

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10620

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1438 AN: 68018

Other (OTH) AF: 0.0595 AC: 126 AN: 2116

Alfa AF: 0.0419 Hom.: 642

Bravo AF: 0.0749

Asia WGS AF: 0.0520 AC: 181 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.5
DANN	Benign	0.67
PhyloP100		-0.73
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: rs3730170; hg19: chr20-57480420; COSMIC: COSV55673089; COSMIC: COSV55673089;