chr17-49991806-TCCCC-T

Position:

• chr17-49991806-TCCCC-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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]

ACMG classification

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906405; hg19: chr17-48069170;