Variant 15-40929862-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_019074.4(DLL4):c.82G>C(p.Gly28Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

DLL4
NM_019074.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.28

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DLL4. . Gene score misZ: 2.7062 (greater than the threshold 3.09). Trascript score misZ: 3.8915 (greater than threshold 3.09). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. GenCC has associacion of the gene with Adams-Oliver syndrome, aplasia cutis congenita, Adams-Oliver syndrome 6.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 15-40929862-G-C is Pathogenic according to our data. Variant chr15-40929862-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 992895.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL4	NM_019074.4 link	c.82G>C	p.Gly28Arg	missense_variant	2/11	ENST00000249749.7	NP_061947.1	Q9NR61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7 link	c.82G>C	p.Gly28Arg	missense_variant	2/11	1	NM_019074.4	ENSP00000249749.5		Q9NR61
DLL4	ENST00000557876.1 link	n.411G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Adams-Oliver syndrome 6

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Center of Medical Genomics-TUH, Thammasat University

Dec 18, 2020

The Gly28Arg variant in DLL4 is a novel in clinical features of Adams-Oliver syndrome, and inherited from unaffected father. However, the Gly28 Ser was revealed higher affinity binding to Notch1 than wild type (Lcuca, et al.2015) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.5

.;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.83

Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);

MVP

0.98

MPC

2.5

ClinPred

1.0

GERP RS

4.6

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over