rs2278163

Positions:

• chr17-49995062-G-A
• chr17-49995062-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005220.3(DLX3):​c.-64C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,568,052 control chromosomes in the GnomAD database, including 57,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6491 hom., cov: 34)
  • Exomes 𝑓: 0.25 (51261 hom.)
• Consequence: DLX3 NM_005220.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-49995062-G-A is Benign according to our data. Variant chr17-49995062-G-A is described in ClinVar as [Benign]. Clinvar id is 324028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLX3	NM_005220.3	c.-64C>T		5_prime_UTR_variant	1/3	ENST00000434704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLX3	ENST00000434704.2	c.-64C>T		5_prime_UTR_variant	1/3	1	NM_005220.3	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41906 AN: 152050 Hom.: 6486 Cov.: 34

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.254 AC: 359783 AN: 1415884 Hom.: 51261 Cov.: 28 AF XY: 0.257 AC XY: 180814 AN XY: 703280

Gnomad4 AFR exome AF: 0.318

Gnomad4 AMR exome AF: 0.249

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.697

Gnomad4 SAS exome AF: 0.386

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.276 AC: 41938 AN: 152168 Hom.: 6491 Cov.: 34 AF XY: 0.281 AC XY: 20890 AN XY: 74400

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.671

Gnomad4 SAS AF: 0.385

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.252

Alfa AF: 0.237 Hom.: 5511

Bravo AF: 0.277

Asia WGS AF: 0.519 AC: 1805 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.74
DANN	Benign	0.69

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: rs2278163; hg19: chr17-48072426; COSMIC: COSV71547551; COSMIC: COSV71547551;