20-58905490-C-T

Variant names:

• chr20-58905490-C-T
• rs199499878
• NM_000516.7:c.530+10C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000516.7(GNAS):​c.530+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,382,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.84

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-58905490-C-T is Benign according to our data. Variant chr20-58905490-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435343.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.530+10C>T		intron_variant	Intron 6 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*436+10C>T		intron_variant	Intron 6 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.530+10C>T		intron_variant	Intron 6 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*436+10C>T		intron_variant	Intron 6 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2462+10C>T		intron_variant	Intron 6 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2417+10C>T		intron_variant	Intron 5 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.533+10C>T		intron_variant	Intron 6 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.488+10C>T		intron_variant	Intron 5 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.356+10C>T		intron_variant	Intron 6 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.356+10C>T		intron_variant	Intron 7 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.356+10C>T		intron_variant	Intron 6 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.311+10C>T		intron_variant	Intron 5 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.311+10C>T		intron_variant	Intron 6 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.311+10C>T		intron_variant	Intron 5 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.311+10C>T		intron_variant	Intron 5 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.311+10C>T		intron_variant	Intron 5 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.311+10C>T		intron_variant	Intron 5 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.311+10C>T		intron_variant	Intron 5 of 11	3		ENSP00000499443.2
GNAS	ENST00000453292.7	c.*391+10C>T		intron_variant	Intron 5 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152056 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251412 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135884

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000198 AC: 244 AN: 1230674 Hom.: 0 Cov.: 20 AF XY: 0.000204 AC XY: 127 AN XY: 623336

Gnomad4 AFR exome AF: 0.0000343

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.0000517

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152056 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74266

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000428 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GNAS-related disorder Benign:1

Dec 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.044
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199499878; hg19: chr20-57480545;