Genetic Variant NM_203486.3:c.425T>C (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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.425T>C	p.Leu142Pro	missense_variant	Exon 4 of 9	ENST00000356433.10	NP_982353.1	Q9NYJ7-2
DLL3	NM_016941.4 link	c.425T>C	p.Leu142Pro	missense_variant	Exon 4 of 8		NP_058637.1	Q9NYJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLL3	ENST00000356433.10 link	c.425T>C	p.Leu142Pro	missense_variant	Exon 4 of 9	2	NM_203486.3	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000205143.4 link	c.425T>C	p.Leu142Pro	missense_variant	Exon 4 of 8	1		ENSP00000205143.3	Q9NYJ7-1
DLL3	ENST00000600437.1 link	n.505T>C		non_coding_transcript_exon_variant	Exon 4 of 6	1
DLL3	ENST00000596614.5 link	c.409+2158T>C		intron_variant	Intron 3 of 3	2		ENSP00000471688.1	M0R177

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 v4.3

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

.;D

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.64

T;T

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Uncertain

-0.077

MutationAssessor

Pathogenic

3.4

M;M

PhyloP100

4.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.020

.;B

Vest4

0.71

MutPred

0.65

Gain of glycosylation at L142 (P = 0.0188);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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over