rs796065348

Positions:

• chr15-40931664-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_019074.4(DLL4):​c.556C>T​(p.Arg186Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLL4 NM_019074.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.91

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]

DLL4 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DLL4. . Gene score misZ 2.7062 (greater than the threshold 3.09). Trascript score misZ 3.8915 (greater than threshold 3.09). GenCC has associacion of gene with Adams-Oliver syndrome, aplasia cutis congenita, Adams-Oliver syndrome 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant 15-40931664-C-T is Pathogenic according to our data. Variant chr15-40931664-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 204373.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-40931664-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL4	NM_019074.4	c.556C>T	p.Arg186Cys	missense_variant	4/11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.556C>T	p.Arg186Cys	missense_variant	4/11	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000559440.1	n.785C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 19, 2015

- -

Adams-Oliver syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Centre of Medical Genetics, University of Antwerp

-

- -

DLL4-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The DLL4 c.556C>T variant is predicted to result in the amino acid substitution p.Arg186Cys. This variant has been reported in at least three individuals, including two affected individuals within the same family, with Adams-Oliver syndrome (Meester et al 2015. PubMed ID: 26299364; Dudoignon et al 2019. PubMed ID: 31654484). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	.;D
REVEL	Uncertain	0.37
Sift	Benign	0.032	.;D
Sift4G	Uncertain	0.056	.;T
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.62		Gain of catalytic residue at L187 (P = 0.0107);Gain of catalytic residue at L187 (P = 0.0107);
MVP		0.73
MPC		2.6
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.90

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: rs796065348; hg19: chr15-41223862;