chrX-70445359-GC-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_021120.4(DLG3):c.159del(p.Tyr54ThrfsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 24)
Consequence
DLG3
NM_021120.4 frameshift
NM_021120.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.05
Genes affected
DLG3 (HGNC:2902): (discs large MAGUK scaffold protein 3) This gene encodes a member of the membrane-associated guanylate kinase protein family. The encoded protein may play a role in clustering of NMDA receptors at excitatory synapses. It may also negatively regulate cell proliferation through interaction with the C-terminal region of the adenomatosis polyposis coli tumor suppressor protein. Mutations in this gene have been associated with X-linked cognitive disability. Alternatively spliced transcript variants have been described. [provided by RefSeq, Oct 2009]
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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 X-70445359-GC-G is Pathogenic according to our data. Variant chrX-70445359-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DLG3 | NM_021120.4 | c.159del | p.Tyr54ThrfsTer67 | frameshift_variant | 1/19 | ENST00000374360.8 | |
DLG3 | XM_006724625.3 | c.159del | p.Tyr54ThrfsTer67 | frameshift_variant | 1/20 | ||
DLG3 | XM_011530883.2 | c.159del | p.Tyr54ThrfsTer67 | frameshift_variant | 1/19 | ||
DLG3 | XM_006724626.3 | c.159del | p.Tyr54ThrfsTer67 | frameshift_variant | 1/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DLG3 | ENST00000374360.8 | c.159del | p.Tyr54ThrfsTer67 | frameshift_variant | 1/19 | 1 | NM_021120.4 | ||
DLG3 | ENST00000194900.8 | c.159del | p.Tyr54ThrfsTer73 | frameshift_variant | 1/21 | 5 | P1 | ||
DLG3 | ENST00000463252.5 | n.225del | non_coding_transcript_exon_variant | 1/19 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 90 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 16, 2022 | PVS1, PM2 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2018 | The c.159delC variant in the DLG3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.159delC variant causes a frameshift starting with codon Tyrosine 54, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 67 of the new reading frame, denoted p.Tyr54ThrfsX67. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.159delC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.159delC as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at