20-58854400-G-T

Variant names:

• chr20-58854400-G-T
• rs587778389
• NM_080425.4:c.1135G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_080425.4(GNAS):​c.1135G>T​(p.Gly379*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNAS NM_080425.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.157
• Publications: 2 publications found

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-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 Gene-Disease associations (from GenCC):

• pseudohypoparathyroidism type 1B

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000293655 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.1135G>T	p.Gly379*	stop_gained	Exon 1 of 13	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13514G>T		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.1135G>T	p.Gly379*	stop_gained	Exon 1 of 12	NP_001397842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.1135G>T	p.Gly379*	stop_gained	Exon 1 of 13	ENSP00000360141.3
	GNAS	ENST00000676826.2		c.1135G>T	p.Gly379*	stop_gained	Exon 1 of 13	ENSP00000504675.2
	GNAS	ENST00000371102.8	TSL:5	c.1135G>T	p.Gly379*	stop_gained	Exon 1 of 12	ENSP00000360143.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000853 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	12
DANN	Benign	0.96
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.16	N
PhyloP100		-0.16
Vest4		0.63
GERP RS		-1.5
Mutation Taster		=98/102	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs587778389; hg19: chr20-57429455;