17-49993439-GCG-CAA

Variant names:

• chr17-49993439-GCG-CAA
• NM_005220.3:c.475_477delCGCinsTTG
• DLX3 p.Arg159Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM1 PP3

The NM_005220.3(DLX3):​c.475_477delCGCinsTTG​(p.Arg159Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLX3 NM_005220.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• Publications: 0 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_005220.3 (DLX3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity DLX3_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005220.3
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.475_477delCGCinsTTG	p.Arg159Leu	missense	N/A	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.475_477delCGCinsTTG	p.Arg159Leu	missense	N/A	ENSP00000389870.2	O60479
	DLX3	ENST00000512495.2	TSL:2	c.115_117delCGCinsTTG	p.Arg39Leu	missense	N/A	ENSP00000449976.1	F8VXG1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-48070803;