rs754069384

Variant names:

• chr15-40929673-C-A
• NM_019074.4:c.5C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-40929673-C-A
• chr15-40929673-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_019074.4(DLL4):​c.5C>A​(p.Ala2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DLL4 NM_019074.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the DLL4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 2.7062 (below the threshold of 3.09). Trascript score misZ: 3.8915 (above the threshold of 3.09). GenCC associations: The gene is linked to Adams-Oliver syndrome, aplasia cutis congenita, Adams-Oliver syndrome 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3281567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL4	NM_019074.4	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 11	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000557876.1	n.334C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393450 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.19e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	0.086
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.42	.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.14	.;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	.;D
Sift4G	Uncertain	0.041	.;D
Polyphen		0.54	P;P
Vest4		0.26
MutPred		0.17		Loss of MoRF binding (P = 0.0196);Loss of MoRF binding (P = 0.0196);
MVP		0.65
MPC		1.2
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-41221871;