17-49969750-A-G

Position:

• chr17-49969750-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_138281.3(DLX4):​c.282A>G​(p.Ala94Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,588,606 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: DLX4 NM_138281.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.1158
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70

Genes affected

DLX4 (HGNC:2917): (distal-less homeobox 4) 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. The DLX proteins are postulated to play a role in forebrain and craniofacial development. Three transcript variants have been described for this gene, however, the full length nature of one variant has not been described. Studies of the two splice variants revealed that one encoded isoform functions as a repressor of the beta-globin gene while the other isoform lacks that function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 17-49969750-A-G is Benign according to our data. Variant chr17-49969750-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 781860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BS2: High AC in GnomAd4 at 263 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLX4	NM_138281.3	c.282A>G	p.Ala94Ala	splice_region_variant, synonymous_variant	1/3	ENST00000240306.5	NP_612138.1
DLX4	XM_047435517.1	c.-3256A>G		5_prime_UTR_variant	2/3		XP_047291473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLX4	ENST00000240306.5	c.282A>G	p.Ala94Ala	splice_region_variant, synonymous_variant	1/3	1	NM_138281.3	ENSP00000240306.3
DLX4	ENST00000503410.1	n.206A>G		splice_region_variant, non_coding_transcript_exon_variant	2/4	4
DLX4	ENST00000505318.2	n.421A>G		splice_region_variant, non_coding_transcript_exon_variant	1/2	3
DLX4	ENST00000706528.1	n.1163A>G		splice_region_variant, non_coding_transcript_exon_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 151928 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00244 AC: 551 AN: 226034 Hom.: 1 AF XY: 0.00236 AC XY: 292 AN XY: 123606

Gnomad AFR exome AF: 0.000401

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00649

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.00246 AC: 3528 AN: 1436560 Hom.: 5 Cov.: 32 AF XY: 0.00240 AC XY: 1714 AN XY: 714410

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.00138

Gnomad4 ASJ exome AF: 0.00630

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000260

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152046 Hom.: 0 Cov.: 30 AF XY: 0.00163 AC XY: 121 AN XY: 74352

Gnomad4 AFR AF: 0.000482

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00172

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.25
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: rs138634383; hg19: chr17-48047114;