Genetic Variant DLL3:p.Arg436Leu (chr19-39507252-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_203486.3(DLL3):c.1307G>T(p.Arg436Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000737 in 1,357,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign 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. R436H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.269

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.1307G>T	p.Arg436Leu	missense_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4 link	c.1307G>T	p.Arg436Leu	missense_variant	Exon 7 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DLL3	ENST00000356433.10 link	c.1307G>T	p.Arg436Leu	missense_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4 link	c.1307G>T	p.Arg436Leu	missense_variant	Exon 7 of 8	1		ENSP00000205143.3
DLL3	ENST00000596614.5 link	c.623G>T	p.Arg208Leu	missense_variant	Exon 4 of 4	2		ENSP00000471688.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1357374

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

669748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27694

American (AMR)

AF:

0.00

AC:

AN:

33468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24112

East Asian (EAS)

AF:

0.00

AC:

AN:

32430

South Asian (SAS)

AF:

0.00

AC:

AN:

76586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5004

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068220

Other (OTH)

AF:

0.00

AC:

AN:

56524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.0067

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;.;D

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

LIST_S2

Benign

0.61

T;D;T

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

0.69

N;.;N

PhyloP100

-0.27

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.0

N;.;N

Sift

Benign

0.30

T;.;T

Sift4G

Benign

0.33

T;T;T

Vest4

0.35

ClinPred

0.65

GERP RS

3.4

Varity_R

0.12

Mutation Taster

=87/13

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over