rs796065351

Variant names:

• chr15-40931691-T-C
• rs796065351
• NM_019074.4:c.583T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_019074.4(DLL4):​c.583T>C​(p.Phe195Leu) 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 (★). Synonymous variant affecting the same amino acid position (i.e. F195F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLL4 NM_019074.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• aplasia cutis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303220 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 15-40931691-T-C is Pathogenic according to our data. Variant chr15-40931691-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 204376.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL4	NM_019074.4	c.583T>C	p.Phe195Leu	missense_variant	Exon 4 of 11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.583T>C	p.Phe195Leu	missense_variant	Exon 4 of 11	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000559440.1	n.812T>C		non_coding_transcript_exon_variant	Exon 1 of 5	2
ENSG00000303220	ENST00000792854.1	n.213-627A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome Pathogenic:1

-

Centre of Medical Genetics, University of Antwerp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		8.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.0	.;D
REVEL	Uncertain	0.59
Sift	Benign	0.041	.;D
Sift4G	Benign	0.092	.;T
Polyphen		0.99	D;D
Vest4		0.72
MutPred		0.78		Gain of ubiquitination at K190 (P = 0.1103);Gain of ubiquitination at K190 (P = 0.1103);
MVP		0.77
MPC		2.4
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.82
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs796065351; hg19: chr15-41223889;