Genetic Variant DLL3:p.Leu142Pro (chr19-39502830-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_203486.3(DLL3):c.425T>C(p.Leu142Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000157 in 1,269,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L142Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.82

Publications

0 publications found

Variant links:

Genes affected

DLL3 (HGNC:2909): (delta like canonical Notch ligand 3) This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. Mutations in this gene cause autosomal recessive spondylocostal dysostosis 1. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DLL3 Gene-Disease associations (from GenCC):

spondylocostal dysostosis 1, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive spondylocostal dysostosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DLL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.425T>C	p.Leu142Pro	missense	Exon 4 of 9	NP_982353.1
	DLL3	NM_016941.4		c.425T>C	p.Leu142Pro	missense	Exon 4 of 8	NP_058637.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLL3	ENST00000356433.10	TSL:2 MANE Select	c.425T>C	p.Leu142Pro	missense	Exon 4 of 9	ENSP00000348810.4
DLL3	ENST00000205143.4	TSL:1	c.425T>C	p.Leu142Pro	missense	Exon 4 of 8	ENSP00000205143.3
DLL3	ENST00000600437.1	TSL:1	n.505T>C		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000157

AC:

AN:

1269856

Hom.:

Cov.:

AF XY:

0.00000160

AC XY:

AN XY:

625594

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25560

American (AMR)

AF:

0.00

AC:

AN:

19624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19826

East Asian (EAS)

AF:

0.00

AC:

AN:

29048

South Asian (SAS)

AF:

0.0000324

AC:

AN:

61798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3630

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1026226

Other (OTH)

AF:

0.00

AC:

AN:

51882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

-0.077

MutationAssessor

Pathogenic

3.4

PhyloP100

4.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

Sift4G

Benign

0.12

Polyphen

0.020

Vest4

0.71

MutPred

0.65

Gain of glycosylation at L142 (P = 0.0188)

MVP

0.85

MPC

1.9

ClinPred

0.98

GERP RS

2.4

Varity_R

0.86

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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