rs797045602
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_201525.4(ADGRG1):c.944_945dup(p.Val316LeufsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
ADGRG1
NM_201525.4 frameshift
NM_201525.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.40
Genes affected
ADGRG1 (HGNC:4512): (adhesion G protein-coupled receptor G1) This gene encodes a member of the G protein-coupled receptor family and regulates brain cortical patterning. The encoded protein binds specifically to transglutaminase 2, a component of tissue and tumor stroma implicated as an inhibitor of tumor progression. Mutations in this gene are associated with a brain malformation known as bilateral frontoparietal polymicrogyria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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;
PP5
?
Variant 16-57655918-A-ATT is Pathogenic according to our data. Variant chr16-57655918-A-ATT is described in ClinVar as [Pathogenic]. Clinvar id is 211096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADGRG1 | NM_201525.4 | c.944_945dup | p.Val316LeufsTer8 | frameshift_variant | 7/14 | ENST00000562631.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADGRG1 | ENST00000562631.7 | c.944_945dup | p.Val316LeufsTer8 | frameshift_variant | 7/14 | 1 | NM_201525.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461848Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0AN XY: 727226
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727226
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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33
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2016 | The c.944_945dupTT pathogenic variant in the GPR56 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.944_945dupTT variant causes a frameshift starting with codon Valine 316, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Val316LeufsX8. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.944_945dupTT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.944_945dupTT as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2020 | This variant has not been reported in the literature in individuals with ADGRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 211096). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ADGRG1 are known to be pathogenic (PMID: 15044805, 20929962). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val316Leufs*8) in the ADGRG1 gene. It is expected to result in an absent or disrupted protein product. - |
Bilateral frontoparietal polymicrogyria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at