rs796065350

chr15-40930649-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_019074.4(DLL4):c.361G>C(p.Ala121Pro) variant causes a missense change. 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:2
• Conservation: PhyloP100: 6.51

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DLL4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 15-40930649-G-C is Pathogenic according to our data. Variant chr15-40930649-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 204375.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-40930649-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL4	NM_019074.4	c.361G>C	p.Ala121Pro	missense_variant	3/11	ENST00000249749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL4	ENST00000249749.7	c.361G>C	p.Ala121Pro	missense_variant	3/11	1	NM_019074.4	P1
DLL4	ENST00000557876.1	n.1198G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

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

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Adams-Oliver syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Centre of Medical Genetics, University of Antwerp

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.57		Gain of disorder (P = 0.1258);Gain of disorder (P = 0.1258);
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs796065350; hg19: chr15-41222847;