chr15-40930085-C-A

Variant names:

• chr15-40930085-C-A
• NM_019074.4:c.305C>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_019074.4(DLL4):​c.305C>A​(p.Pro102His) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLL4 NM_019074.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 5 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, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL4	NM_019074.4	c.305C>A	p.Pro102His	missense_variant	Exon 2 of 11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.305C>A	p.Pro102His	missense_variant	Exon 2 of 11	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000557876.1	n.634C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 19, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.65	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.0	.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		1.0	D;D
Vest4		0.76
MutPred		0.39		Gain of catalytic residue at P102 (P = 0.1189);Gain of catalytic residue at P102 (P = 0.1189);
MVP		0.89
MPC		2.1
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.84
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-41222283;