Variant 20-58840055-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016592.5(GNAS):c.-52A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,596,376 control chromosomes in the GnomAD database, including 329,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26724 hom., cov: 29)

Exomes 𝑓: 0.64 ( 302495 hom. )

Consequence

GNAS
NM_016592.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0540

Variant links:

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 links:

GNAS-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

GNAS-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 20-58840055-A-G is Benign according to our data. Variant chr20-58840055-A-G is described in ClinVar as [Benign]. Clinvar id is 1280334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_016592.5 linkuse as main transcript	c.-52A>G		5_prime_UTR_variant	1/13	ENST00000371075.7	NP_057676.1
GNAS-AS1	NR_002785.2 linkuse as main transcript	n.819+1882T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7 linkuse as main transcript	c.-52A>G		5_prime_UTR_variant	1/13	1	NM_016592.5	ENSP00000360115		O95467-1
GNAS-AS1	ENST00000424094.6 linkuse as main transcript	n.819+1882T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.585

AC:

88299

AN:

151000

Hom.:

26697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.434

Gnomad AMI

AF:

0.726

Gnomad AMR

AF:

0.597

Gnomad ASJ

AF:

0.513

Gnomad EAS

AF:

0.806

Gnomad SAS

AF:

0.682

Gnomad FIN

AF:

0.695

Gnomad MID

AF:

0.452

Gnomad NFE

AF:

0.635

Gnomad OTH

AF:

0.559

GnomAD4 exome

AF:

0.645

AC:

931470

AN:

1445258

Hom.:

302495

Cov.:

AF XY:

0.645

AC XY:

464481

AN XY:

719630

show subpopulations

Gnomad4 AFR exome

AF:

0.423

Gnomad4 AMR exome

AF:

0.674

Gnomad4 ASJ exome

AF:

0.508

Gnomad4 EAS exome

AF:

0.777

Gnomad4 SAS exome

AF:

0.685

Gnomad4 FIN exome

AF:

0.690

Gnomad4 NFE exome

AF:

0.645

Gnomad4 OTH exome

AF:

0.626

GnomAD4 genome

AF:

0.585

AC:

88376

AN:

151118

Hom.:

26724

Cov.:

AF XY:

0.590

AC XY:

43547

AN XY:

73852

show subpopulations

Gnomad4 AFR

AF:

0.435

Gnomad4 AMR

AF:

0.597

Gnomad4 ASJ

AF:

0.513

Gnomad4 EAS

AF:

0.806

Gnomad4 SAS

AF:

0.683

Gnomad4 FIN

AF:

0.695

Gnomad4 NFE

AF:

0.635

Gnomad4 OTH

AF:

0.565

Alfa

AF:

0.614

Hom.:

27483

Bravo

AF:

0.570

Asia WGS

AF:

0.709

AC:

2464

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Oct 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.69

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over