NM_019074.4:c.949A>C

Variant names:

• chr15-40934646-A-C
• rs1555393027
• NM_019074.4:c.949A>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.949A>C​(p.Thr317Pro) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLL4 NM_019074.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.29

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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 15-40934646-A-C is Pathogenic according to our data. Variant chr15-40934646-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523590.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.949A>C	p.Thr317Pro	missense_variant	Exon 7 of 11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.949A>C	p.Thr317Pro	missense_variant	Exon 7 of 11	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000559440.1	n.1178A>C		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adams-Oliver syndrome 6 Pathogenic:1

Dec 01, 2017

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	4.1	H;H
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.4	.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	.;D
Sift4G	Uncertain	0.010	.;D
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.49		Loss of phosphorylation at T317 (P = 0.0579);Loss of phosphorylation at T317 (P = 0.0579);
MVP		0.77
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.92
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: rs1555393027; hg19: chr15-41226844;