Variant 20-58840400-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_016592.5(GNAS):c.294C>T(p.Pro98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,613,458 control chromosomes in the GnomAD database, including 1,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.048 ( 283 hom., cov: 32)

Exomes 𝑓: 0.031 ( 940 hom. )

Consequence

GNAS
NM_016592.5 synonymous

Scores

Clinical Significance

Benign/Likely benign no assertion criteria provided B:2

Conservation

PhyloP100: 0.125

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 20-58840400-C-T is Benign according to our data. Variant chr20-58840400-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1205855.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-58840400-C-T is described in Lovd as [Benign]. Variant chr20-58840400-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.125 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_016592.5 linkuse as main transcript	c.294C>T	p.Pro98=	synonymous_variant	1/13	ENST00000371075.7
GNAS-AS1	NR_002785.2 linkuse as main transcript	n.819+1537G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7 linkuse as main transcript	c.294C>T	p.Pro98=	synonymous_variant	1/13	1	NM_016592.5		O95467-1
GNAS-AS1	ENST00000424094.6 linkuse as main transcript	n.819+1537G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0479

AC:

7284

AN:

152114

Hom.:

274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00774

Gnomad SAS

AF:

0.0413

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0297

Gnomad OTH

AF:

0.0445

GnomAD3 exomes

AF:

0.0301

AC:

7510

AN:

249632

Hom.:

177

AF XY:

0.0300

AC XY:

4053

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.00517

Gnomad SAS exome

AF:

0.0411

Gnomad FIN exome

AF:

0.00898

Gnomad NFE exome

AF:

0.0296

Gnomad OTH exome

AF:

0.0297

GnomAD4 exome

AF:

0.0314

AC:

45843

AN:

1461226

Hom.:

940

Cov.:

AF XY:

0.0315

AC XY:

22930

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.110

Gnomad4 AMR exome

AF:

0.0167

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.00302

Gnomad4 SAS exome

AF:

0.0409

Gnomad4 FIN exome

AF:

0.0109

Gnomad4 NFE exome

AF:

0.0311

Gnomad4 OTH exome

AF:

0.0345

GnomAD4 genome

AF:

0.0481

AC:

7322

AN:

152232

Hom.:

283

Cov.:

AF XY:

0.0456

AC XY:

3397

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.106

Gnomad4 AMR

AF:

0.0264

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00775

Gnomad4 SAS

AF:

0.0417

Gnomad4 FIN

AF:

0.00706

Gnomad4 NFE

AF:

0.0297

Gnomad4 OTH

AF:

0.0545

Alfa

AF:

0.0359

Hom.:

Bravo

AF:

0.0511

Asia WGS

AF:

0.0730

AC:

254

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.94

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