rs587778387
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016592.5(GNAS):c.354_365delAATCGAGTCCGA(p.Ile119_Glu122del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
GNAS
NM_016592.5 disruptive_inframe_deletion
NM_016592.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.41
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GNAS | ENST00000371075.7 | c.354_365delAATCGAGTCCGA | p.Ile119_Glu122del | disruptive_inframe_deletion | Exon 1 of 13 | 1 | NM_016592.5 | ENSP00000360115.3 | ||
| GNAS | ENST00000453292.7 | c.354_365delAATCGAGTCCGA | p.Ile119_Glu122del | disruptive_inframe_deletion | Exon 1 of 12 | 5 | ENSP00000392000.2 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249580Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135124
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461206Hom.: 0 AF XY: 0.0000220 AC XY: 16AN XY: 726980
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GnomAD4 genome 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
GNAS-related disorder Uncertain:1
Jan 16, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
The GNAS c.354_365del12 variant is predicted to result in an in-frame deletion (p.Ile119_Glu122del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population
- -
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at