rs1247027543

Positions:

• chr15-40936384-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_019074.4(DLL4):​c.1397G>A​(p.Cys466Tyr) variant causes a missense change involving the alteration of a 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:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 9 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, 0.994
• PP5: Variant 15-40936384-G-A is Pathogenic according to our data. Variant chr15-40936384-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 523592.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL4	NM_019074.4	c.1397G>A	p.Cys466Tyr	missense_variant	9/11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.1397G>A	p.Cys466Tyr	missense_variant	9/11	1	NM_019074.4	ENSP00000249749	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Centre of Medical Genetics, University of Antwerp

Dec 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.5	D
MutationAssessor	Pathogenic	4.9	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-11	.;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.93		Loss of disorder (P = 0.042);Loss of disorder (P = 0.042);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1247027543; hg19: chr15-41228582;