dbSNP rs796065348: DLL4:p.Arg186Cys (chr15-40931664-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_019074.4(DLL4):c.556C>T(p.Arg186Cys) variant causes a missense change involving the alteration of a non-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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

DLL4
NM_019074.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.91

Publications

3 publications found

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]

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

DLL4 links:

ENSG00000303220 (HGNC:):

ENSG00000303220 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

PP5

Variant 15-40931664-C-T is Pathogenic according to our data. Variant chr15-40931664-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 204373.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 link	c.556C>T	p.Arg186Cys	missense_variant	Exon 4 of 11	ENST00000249749.7	NP_061947.1	Q9NR61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLL4	ENST00000249749.7 link	c.556C>T	p.Arg186Cys	missense_variant	Exon 4 of 11	1	NM_019074.4	ENSP00000249749.5	Q9NR61
DLL4	ENST00000559440.1 link	n.785C>T		non_coding_transcript_exon_variant	Exon 1 of 5	2
ENSG00000303220	ENST00000792854.1 link	n.213-600G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Adams-Oliver syndrome 6

Pathogenic:1

Aug 19, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Adams-Oliver syndrome

Pathogenic:1

Centre of Medical Genetics, University of Antwerp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

DLL4-related disorder

Pathogenic:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DLL4 c.556C>T variant is predicted to result in the amino acid substitution p.Arg186Cys. This variant has been reported in at least three individuals, including two affected individuals within the same family, with Adams-Oliver syndrome (Meester et al 2015. PubMed ID: 26299364; Dudoignon et al 2019. PubMed ID: 31654484). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.062

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

.;D

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

-0.087

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

2.9

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.9

.;D

REVEL

Uncertain

0.37

Sift

Benign

0.032

.;D

Sift4G

Uncertain

0.056

.;T

Polyphen

1.0

D;D

Vest4

0.79

MutPred

0.62

Gain of catalytic residue at L187 (P = 0.0107);Gain of catalytic residue at L187 (P = 0.0107);

MVP

0.73

MPC

2.6

ClinPred

0.99

GERP RS

5.5

Varity_R

0.66

gMVP

0.90

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over