rs33937843

chr17-49994861-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005220.3(DLX3):c.138C>T(p.Pro46=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0614 in 1,614,156 control chromosomes in the GnomAD database, including 5,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (929 hom., cov: 34)
  • Exomes 𝑓: 0.059 (4454 hom.)
• Consequence: DLX3 NM_005220.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.174

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 17-49994861-G-A is Benign according to our data. Variant chr17-49994861-G-A is described in ClinVar as [Benign]. Clinvar id is 259675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-49994861-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.174 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLX3	NM_005220.3	c.138C>T	p.Pro46=	synonymous_variant	1/3	ENST00000434704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLX3	ENST00000434704.2	c.138C>T	p.Pro46=	synonymous_variant	1/3	1	NM_005220.3	P1

Frequencies

GnomAD3 genomes AF: 0.0859 AC: 13069 AN: 152166 Hom.: 927 Cov.: 34

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0812

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0632

GnomAD3 exomes AF: 0.0859 AC: 21594 AN: 251386 Hom.: 1524 AF XY: 0.0850 AC XY: 11555 AN XY: 135900

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.181

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0390

Gnomad OTH exome AF: 0.0629

GnomAD4 exome AF: 0.0588 AC: 86024 AN: 1461872 Hom.: 4454 Cov.: 32 AF XY: 0.0616 AC XY: 44768 AN XY: 727240

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.0181

Gnomad4 NFE exome AF: 0.0407

Gnomad4 OTH exome AF: 0.0664

GnomAD4 genome AF: 0.0860 AC: 13098 AN: 152284 Hom.: 929 Cov.: 34 AF XY: 0.0871 AC XY: 6487 AN XY: 74470

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.0813

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.179

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0583 Hom.: 220

Bravo AF: 0.0953

Asia WGS AF: 0.205 AC: 715 AN: 3478

EpiCase AF: 0.0391

EpiControl AF: 0.0374

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Tricho-dento-osseous syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	10
Dann	Benign	0.94

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: rs33937843; hg19: chr17-48072225; COSMIC: COSV71547533; COSMIC: COSV71547533;