chr17-49991806-T-TC

Variant names:

• chr17-49991806-T-TC
• rs1057518764
• NM_005220.3:c.574dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005220.3(DLX3):​c.574dupG​(p.Glu192GlyfsTer10) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLX3 NM_005220.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.16
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 8 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 0.336 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-49991806-T-TC is Pathogenic according to our data. Variant chr17-49991806-T-TC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 373912.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLX3	NM_005220.3	c.574dupG	p.Glu192GlyfsTer10	frameshift_variant	Exon 3 of 3	ENST00000434704.2	NP_005211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLX3	ENST00000434704.2	c.574dupG	p.Glu192GlyfsTer10	frameshift_variant	Exon 3 of 3	1	NM_005220.3	ENSP00000389870.2
DLX3	ENST00000512495.2	c.214dupG	p.Glu72GlyfsTer10	frameshift_variant	Exon 2 of 2	2		ENSP00000449976.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amelogenesis imperfecta;C0345030:Peripheral pulmonary artery stenosis Pathogenic:1

Jun 10, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

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: rs1057518764; hg19: chr17-48069170;