Genetic Variant DLL4:p.Gly98Ala (chr15-40930073-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019074.4(DLL4):c.293G>C(p.Gly98Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DLL4
NM_019074.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.74

Publications

0 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: Labcorp Genetics (formerly Invitae), G2P
Adams-Oliver syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
aplasia cutis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DLL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1369254).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019074.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL4	NM_019074.4	MANE Select	c.293G>C	p.Gly98Ala	missense	Exon 2 of 11	NP_061947.1	Q9NR61

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLL4	ENST00000249749.7	TSL:1 MANE Select	c.293G>C	p.Gly98Ala	missense	Exon 2 of 11	ENSP00000249749.5	Q9NR61
DLL4	ENST00000878560.1		c.266G>C	p.Gly89Ala	missense	Exon 2 of 11	ENSP00000548619.1
DLL4	ENST00000878561.1		c.293G>C	p.Gly98Ala	missense	Exon 2 of 8	ENSP00000548620.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000431

AC:

AN:

231954

AF XY:

0.00000785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455210

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723550

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33340

American (AMR)

AF:

0.0000455

AC:

AN:

43926

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.00

AC:

AN:

85390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109604

Other (OTH)

AF:

0.00

AC:

AN:

60070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.40

Eigen

Benign

-0.13

Eigen_PC

Benign

0.033

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.78

M_CAP

Benign

0.019

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.0

PhyloP100

2.7

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.21

REVEL

Benign

0.15

Sift

Benign

0.47

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.10

MutPred

0.37

Loss of disorder (P = 0.1273)

MVP

0.70

MPC

1.2

ClinPred

0.13

GERP RS

4.6

Varity_R

0.19

gMVP

0.69

Mutation Taster

=86/14

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over