rs2303466

Variant names:

• chr17-49993514-C-T
• rs2303466
• NM_005220.3:c.402G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005220.3(DLX3):​c.402G>A​(p.Thr134Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 1,613,220 control chromosomes in the GnomAD database, including 31,782 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3009 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28773 hom.)
• Consequence: DLX3 NM_005220.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.102
• Publications: 21 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 17-49993514-C-T is Benign according to our data. Variant chr17-49993514-C-T is described in ClinVar as Benign. ClinVar VariationId is 259676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

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.402G>A	p.Thr134Thr	synonymous	Exon 2 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.402G>A	p.Thr134Thr	synonymous	Exon 2 of 3	ENSP00000389870.2	O60479
	DLX3	ENST00000512495.2	TSL:2	c.42G>A	p.Thr14Thr	synonymous	Exon 1 of 2	ENSP00000449976.1	F8VXG1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28235 AN: 151992 Hom.: 3010 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.207 AC: 51648 AN: 249274 AF XY: 0.209

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.239

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.188 AC: 275168 AN: 1461110 Hom.: 28773 Cov.: 34 AF XY: 0.189 AC XY: 137141 AN XY: 726888

African (AFR) AF: 0.150 AC: 5022 AN: 33456

American (AMR) AF: 0.120 AC: 5377 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6578 AN: 26108

East Asian (EAS) AF: 0.498 AC: 19759 AN: 39658

South Asian (SAS) AF: 0.205 AC: 17658 AN: 86222

European-Finnish (FIN) AF: 0.233 AC: 12403 AN: 53274

Middle Eastern (MID) AF: 0.225 AC: 1300 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 195009 AN: 1111606

Other (OTH) AF: 0.200 AC: 12062 AN: 60346

GnomAD4 genome AF: 0.186 AC: 28240 AN: 152110 Hom.: 3009 Cov.: 33 AF XY: 0.190 AC XY: 14136 AN XY: 74354

African (AFR) AF: 0.152 AC: 6302 AN: 41542

American (AMR) AF: 0.143 AC: 2190 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3470

East Asian (EAS) AF: 0.488 AC: 2501 AN: 5124

South Asian (SAS) AF: 0.191 AC: 922 AN: 4828

European-Finnish (FIN) AF: 0.238 AC: 2519 AN: 10596

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.180 AC: 12207 AN: 67932

Other (OTH) AF: 0.185 AC: 391 AN: 2116

Alfa AF: 0.182 Hom.: 1220

Bravo AF: 0.178

Asia WGS AF: 0.311 AC: 1078 AN: 3476

EpiCase AF: 0.183

EpiControl AF: 0.181

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism (2)
-	-	1	not specified (1)
-	-	1	Tricho-dento-osseous syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.6
DANN	Benign	0.97
PhyloP100		0.10
PromoterAI		-0.010	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303466; hg19: chr17-48070878; COSMIC: COSV71547566; COSMIC: COSV71547566;