20-58891811-C-T

Variant names:

• chr20-58891811-C-T
• rs1057518907
• NM_000516.7:c.85C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000516.7(GNAS):​c.85C>T​(p.Gln29*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAS NM_000516.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.20

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 144 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58891811-C-T is Pathogenic according to our data. Variant chr20-58891811-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 374113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58891811-C-T is described in Lovd as [Likely_pathogenic]. Variant chr20-58891811-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.85C>T	p.Gln29*	stop_gained	Exon 1 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-3801C>T		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.85C>T	p.Gln29*	stop_gained	Exon 1 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000354359.12	c.85C>T	p.Gln29*	stop_gained	Exon 1 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.85C>T	p.Gln29*	stop_gained	Exon 1 of 12	1		ENSP00000360136.3
GNAS	ENST00000371075.7	c.*43-3801C>T		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-3801C>T		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-3801C>T		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+2458C>T		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+2262C>T		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-3801C>T		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-3801C>T		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-3801C>T		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+2458C>T		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+2903C>T		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+2262C>T		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+2993C>T		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000461152.6	c.*51+1022C>T		intron_variant	Intron 1 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-3801C>T		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1142418 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 566350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln29*) in the GNAS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNAS are known to be pathogenic (PMID: 11784876, 23281139, 23796510, 25802881). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Albright hereditary osteodystrophy or pseudohypoparathyroidism (PMID: 12970262, 21525160, 29059381). ClinVar contains an entry for this variant (Variation ID: 374113). For these reasons, this variant has been classified as Pathogenic. -

Feb 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17164301, 25894639, 23533243, 21525160, 24651309, 25525159, 29059381, 20427508, 25464124, 23281139, 23796510, 24127307, 19465898, 12970262, 29379892, 29970488, 31886927, 23884777) -

Pseudohypoparathyroidism type 1B Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. This variant was inherited from a parent. -

Cushing syndrome;C0033806:Pseudohypoparathyroidism;C0033835:Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C4540135:Pituitary adenoma 3, multiple types Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypocalcemia;C0028754:Obesity;C0039621:Tetany;C0151811:Subcutaneous nodule;C0221357:Brachydactyly;C0239479:Round face;C0338656:Cognitive impairment;C0349588:Short stature Pathogenic:1

May 29, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Benign	0.056
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.69
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1057518907; hg19: chr20-57466866; COSMIC: COSV55670958; COSMIC: COSV55670958;