rs387906405

Variant names:

• chr17-49991806-TCCCC-T
• rs387906405
• NM_005220.3:c.571_574delGGGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_005220.3(DLX3):​c.571_574delGGGG​(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 (★★). ClinVar reports functional evidence for this variant: "SCV001786340: 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" and additional evidence is available in ClinVar. 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:6
• Conservation: PhyloP100: 7.91
• Publications: 12 publications found

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]

DLX3 Gene-Disease associations (from GenCC):

• tricho-dento-osseous syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 3 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786340: 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); SCV002201324: Experimental studies have shown that this premature translational stop signal affects DLX3 function (PMID: 17950683, 18492670, 20510228, 21520071, 27924851).; SCV004111481: "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)."
• 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 VariationId is 9072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005220.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLX3	NM_005220.3	MANE Select	c.571_574delGGGG	p.Gly191ArgfsTer66	frameshift	Exon 3 of 3	NP_005211.1	O60479

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLX3	ENST00000434704.2	TSL:1 MANE Select	c.571_574delGGGG	p.Gly191ArgfsTer66	frameshift	Exon 3 of 3	ENSP00000389870.2	O60479
	DLX3	ENST00000512495.2	TSL:2	c.211_214delGGGG	p.Gly71ArgfsTer66	frameshift	Exon 2 of 2	ENSP00000449976.1	F8VXG1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	DLX3-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Tricho-dento-osseous syndrome (1)
1	-	-	Tricho-dento-osseous syndrome;C1863012:Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906405; hg19: chr17-48069170;