20-58903393-A-T

Position:

• chr20-58903393-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000516.7(GNAS):​c.258-138A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 791,184 control chromosomes in the GnomAD database, including 31,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7086 hom., cov: 31)
  • Exomes 𝑓: 0.26 (23971 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.488

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 20-58903393-A-T is Benign according to our data. Variant chr20-58903393-A-T is described in ClinVar as [Benign]. Clinvar id is 1247589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.258-138A>T		intron_variant		ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*161-135A>T		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.258-138A>T		intron_variant		1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*161-135A>T		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2187-135A>T		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2142-135A>T		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.258-135A>T		intron_variant		1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.213-135A>T		intron_variant		1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.81-135A>T		intron_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.81-135A>T		intron_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.81-135A>T		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.36-135A>T		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.36-135A>T		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.36-135A>T		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.36-135A>T		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.36-135A>T		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.36-135A>T		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.36-135A>T		intron_variant		3		ENSP00000499443.2
GNAS	ENST00000461152.6	c.*125-135A>T		intron_variant		5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*116-135A>T		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44781 AN: 152024 Hom.: 7078 Cov.: 31

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.279

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.280

GnomAD4 exome AF: 0.261 AC: 167072 AN: 639042 Hom.: 23971 Cov.: 8 AF XY: 0.256 AC XY: 87276 AN XY: 340836

Gnomad4 AFR exome AF: 0.370

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.333

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.268

GnomAD4 genome AF: 0.295 AC: 44828 AN: 152142 Hom.: 7086 Cov.: 31 AF XY: 0.291 AC XY: 21668 AN XY: 74378

Gnomad4 AFR AF: 0.372

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.289

Gnomad4 EAS AF: 0.0940

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.342

Gnomad4 NFE AF: 0.289

Gnomad4 OTH AF: 0.287

Alfa AF: 0.201 Hom.: 504

Bravo AF: 0.289

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2295583; hg19: chr20-57478448; COSMIC: COSV55681638; COSMIC: COSV55681638;