15-40929827-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_019074.4(DLL4):c.67-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,609,742 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (59 hom., cov: 33)
  • Exomes 𝑓: 0.013 (188 hom.)
• Consequence: DLL4 NM_019074.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.457

Genes affected

DLL4 (HGNC:2910): (delta like canonical Notch ligand 4) This gene is a homolog of the Drosophila delta gene. The delta gene family encodes Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 15-40929827-C-T is Benign according to our data. Variant chr15-40929827-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1168604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL4	NM_019074.4	c.67-20C>T		intron_variant		ENST00000249749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL4	ENST00000249749.7	c.67-20C>T		intron_variant		1	NM_019074.4	P1
DLL4	ENST00000557876.1	n.396-20C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3184 AN: 152240 Hom.: 59 Cov.: 33

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0137 AC: 3272 AN: 238708 Hom.: 36 AF XY: 0.0138 AC XY: 1802 AN XY: 130670

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.00118

Gnomad SAS exome AF: 0.00758

Gnomad FIN exome AF: 0.00164

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0126 AC: 18421 AN: 1457384 Hom.: 188 Cov.: 32 AF XY: 0.0127 AC XY: 9233 AN XY: 725048

Gnomad4 AFR exome AF: 0.0466

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.00671

Gnomad4 FIN exome AF: 0.00276

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0210 AC: 3192 AN: 152358 Hom.: 59 Cov.: 33 AF XY: 0.0197 AC XY: 1471 AN XY: 74504

Gnomad4 AFR AF: 0.0394

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0201 Hom.: 20

Bravo AF: 0.0230

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign/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	clinical testing	GeneDx	Sep 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	12
Dann	Benign	0.96

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: rs3212277; hg19: chr15-41222025;