20-58890223-G-A

Variant names:

• chr20-58890223-G-A
• rs9679845
• ENST00000461152.6:c.343G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_080425.4(GNAS):​c.2069-5389G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.042 in 151,448 control chromosomes in the GnomAD database, including 167 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 0.042 (167 hom., cov: 32)
• Consequence: GNAS NM_080425.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.042 (6355/151448) while in subpopulation AMR AF = 0.0521 (792/15216). AF 95% confidence interval is 0.049. There are 167 homozygotes in GnomAd4. There are 3063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6355 AD,Mitochondrial,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2069-5389G>A		intron	N/A	NP_536350.2	Q5JWF2-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*43-5389G>A		intron	N/A	NP_057676.1	O95467-1
	GNAS	NM_001410913.1		c.2069-5389G>A		intron	N/A	NP_001397842.1	Q5JWE9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000461152.6	TSL:5	c.343G>A	p.Glu115Lys	missense	Exon 1 of 3	ENSP00000499274.1	A0A590UJ46
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2069-5389G>A		intron	N/A	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*43-5389G>A		intron	N/A	ENSP00000360115.3	O95467-1

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6348 AN: 151336 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0572

Gnomad EAS AF: 0.00564

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0477

Gnomad OTH AF: 0.0538

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

GnomAD4 genome AF: 0.0420 AC: 6355 AN: 151448 Hom.: 167 Cov.: 32 AF XY: 0.0414 AC XY: 3063 AN XY: 74036

African (AFR) AF: 0.0384 AC: 1592 AN: 41476

American (AMR) AF: 0.0521 AC: 792 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0572 AC: 198 AN: 3460

East Asian (EAS) AF: 0.00565 AC: 29 AN: 5130

South Asian (SAS) AF: 0.0140 AC: 67 AN: 4800

European-Finnish (FIN) AF: 0.0261 AC: 269 AN: 10300

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0478 AC: 3236 AN: 67760

Other (OTH) AF: 0.0538 AC: 113 AN: 2102

Alfa AF: 0.0423 Hom.: 141

Bravo AF: 0.0447

Asia WGS AF: 0.0130 AC: 45 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.83
CADD	Benign	16
DANN	Benign	0.88
PhyloP100		2.4
PromoterAI		0.00080	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9679845; hg19: chr20-57465278;