15-40929862-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DLL4
• 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	UniProt
DLL4	NM_019074.4	c.82G>C	p.Gly28Arg	missense_variant	2/11	ENST00000249749.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL4	ENST00000249749.7	c.82G>C	p.Gly28Arg	missense_variant	2/11	1	NM_019074.4	P1
DLL4	ENST00000557876.1	n.411G>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	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	D
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.

Other links and lift over

hg19: chr15-41222060;