rs777481123

Variant names:

• chr15-40934986-C-G
• rs777481123
• NM_019074.4:c.1109C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-40934986-C-G
• chr15-40934986-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_019074.4(DLL4):​c.1109C>G​(p.Pro370Arg) 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. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P370L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLL4 NM_019074.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL4	NM_019074.4	c.1109C>G	p.Pro370Arg	missense_variant	Exon 8 of 11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.1109C>G	p.Pro370Arg	missense_variant	Exon 8 of 11	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000559440.1	n.*65C>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.7	.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.029	.;D
Sift4G	Uncertain	0.037	.;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.75		Gain of solvent accessibility (P = 0.0971);Gain of solvent accessibility (P = 0.0971);
MVP		0.89
MPC		1.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.74
gMVP		0.92
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs777481123; hg19: chr15-41227184;