rs2278163

Variant names:

• chr17-49995062-G-A
• rs2278163
• NM_005220.3:c.-64C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.67
• Publications: 26 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
DLX3	NM_005220.3	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	ENST00000434704.2	NP_005211.1
DLX3	NM_005220.3	c.-64C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000434704.2	NP_005211.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLX3	ENST00000434704.2	c.-64C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	1	NM_005220.3	ENSP00000389870.2
DLX3	ENST00000434704.2	c.-64C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_005220.3	ENSP00000389870.2

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

African (AFR) AF: 0.318 AC: 10400 AN: 32676

American (AMR) AF: 0.249 AC: 9969 AN: 39978

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7200 AN: 25684

East Asian (EAS) AF: 0.697 AC: 26861 AN: 38534

South Asian (SAS) AF: 0.386 AC: 32145 AN: 83246

European-Finnish (FIN) AF: 0.254 AC: 10321 AN: 40562

Middle Eastern (MID) AF: 0.282 AC: 1164 AN: 4122

European-Non Finnish (NFE) AF: 0.225 AC: 245675 AN: 1091996

Other (OTH) AF: 0.272 AC: 16048 AN: 59086

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

African (AFR) AF: 0.315 AC: 13099 AN: 41522

American (AMR) AF: 0.228 AC: 3495 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1014 AN: 3472

East Asian (EAS) AF: 0.671 AC: 3459 AN: 5154

South Asian (SAS) AF: 0.385 AC: 1858 AN: 4826

European-Finnish (FIN) AF: 0.253 AC: 2680 AN: 10590

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15438 AN: 67986

Other (OTH) AF: 0.252 AC: 533 AN: 2116

Alfa AF: 0.246 Hom.: 17013

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypomaturation-hypoplastic amelogenesis imperfecta with taurodontism Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.7
PromoterAI		-0.063	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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