rs387906405
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_005220.3(DLX3):c.571_574del(p.Gly191ArgfsTer66) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G191G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
DLX3
NM_005220.3 frameshift
NM_005220.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
DLX3 (HGNC:2916): (distal-less homeobox 3) Many vertebrate homeo box-containing genes have been identified on the basis of their sequence similarity with Drosophila developmental genes. Members of the Dlx gene family contain a homeobox that is related to that of Distal-less (Dll), a gene expressed in the head and limbs of the developing fruit fly. The Distal-less (Dlx) family of genes comprises at least 6 different members, DLX1-DLX6. Trichodentoosseous syndrome (TDO), an autosomal dominant condition, has been correlated with DLX3 gene mutation. This gene is located in a tail-to-tail configuration with another member of the gene family on the long arm of chromosome 17. Mutations in this gene have been associated with the autosomal dominant conditions trichodentoosseous syndrome and amelogenesis imperfecta with taurodontism. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.339 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-49991806-TCCCC-T is Pathogenic according to our data. Variant chr17-49991806-TCCCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 9072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DLX3 | NM_005220.3 | c.571_574del | p.Gly191ArgfsTer66 | frameshift_variant | 3/3 | ENST00000434704.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DLX3 | ENST00000434704.2 | c.571_574del | p.Gly191ArgfsTer66 | frameshift_variant | 3/3 | 1 | NM_005220.3 | P1 | |
DLX3 | ENST00000512495.2 | c.211_214del | p.Gly71ArgfsTer66 | frameshift_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change creates a premature translational stop signal (p.Gly191Argfs*66) in the DLX3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 97 amino acid(s) of the DLX3 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Trichodontoosseous syndrome (PMID: 9467018). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9072). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DLX3 function (PMID: 17950683, 18492670, 20510228, 21520071, 27924851). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2023 | Published functional studies demonstrate a damaging effect as this variant causes defective transcriptional activity and impairs the expression of cell cycle regulatory proteins and skin differentiation markers (Duverger et al., 2008; Di Constanzo et al., 2011); Frameshift variant predicted to result in protein truncation, as the last 97 amino acids are replaced with 65 different amino acids, and one other loss-of-function variant has been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27924851, 21520071, 17950683, 20510228, 22671030, 18203197, 18362318, 9783705, 18492670) - |
DLX3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 16, 2023 | The DLX3 c.571_574delGGGG variant is predicted to result in a frameshift and premature protein termination (p.Gly191Argfs*66). This variant has been previously reported in individuals with tricho-dento-osseous syndrome (Price et al. 1998. PubMed ID: 9467018; Price et al. 1998. PubMed ID: 9783705; Nguyen et al. 2013. PubMed ID: 22671030). In vitro functional studies found that the presence of this variant delayed cellular senescence, and enhanced osteoblastic differentiation and bone formation (Choi et al. 2008. PubMed ID: 17950683; Zhao et al 2016. PubMed ID: 27924851). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in DLX3 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Tricho-dento-osseous syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at