chr20-58890223-G-A

Position:

• chr20-58890223-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000461152.6(GNAS):​c.343G>A​(p.Glu115Lys) variant causes a missense 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. 4/4 in silico tools predict 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 ENST00000461152.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 167 SM,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*43-5389G>A		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000461152.6	c.343G>A	p.Glu115Lys	missense_variant	1/3	5		ENSP00000499274.1
GNAS	ENST00000371075.7	c.*43-5389G>A		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-5389G>A		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-5389G>A		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+870G>A		intron_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+674G>A		intron_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-5389G>A		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-5389G>A		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-5389G>A		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+870G>A		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+1315G>A		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+674G>A		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+1405G>A		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000453292.7	c.*43-5389G>A		intron_variant		5		ENSP00000392000.2

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

Gnomad4 AFR AF: 0.0384

Gnomad4 AMR AF: 0.0521

Gnomad4 ASJ AF: 0.0572

Gnomad4 EAS AF: 0.00565

Gnomad4 SAS AF: 0.0140

Gnomad4 FIN AF: 0.0261

Gnomad4 NFE AF: 0.0478

Gnomad4 OTH AF: 0.0538

Alfa AF: 0.0391 Hom.: 89

Bravo AF: 0.0447

Asia WGS AF: 0.0130 AC: 45 AN: 3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	16
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9679845; hg19: chr20-57465278;