Menu
GeneBe

15-40930085-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_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

Scores

5
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, DLL4
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DLL4NM_019074.4 linkuse as main transcriptc.305C>A p.Pro102His missense_variant 2/11 ENST00000249749.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DLL4ENST00000249749.7 linkuse as main transcriptc.305C>A p.Pro102His missense_variant 2/111 NM_019074.4 P1
DLL4ENST00000557876.1 linkuse as main transcriptn.634C>A non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 19, 2022Not 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
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Uncertain
0.57
D
MutationAssessor
Pathogenic
2.9
M;M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.72
T
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; API