Variant 19-39502939-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_203486.3(DLL3):c.534C>G(p.Cys178Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,440,640 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.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.33

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL3	NM_203486.3 linkuse as main transcript	c.534C>G	p.Cys178Trp	missense_variant	4/9	ENST00000356433.10
DLL3	NM_016941.4 linkuse as main transcript	c.534C>G	p.Cys178Trp	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL3	ENST00000356433.10 linkuse as main transcript	c.534C>G	p.Cys178Trp	missense_variant	4/9	2	NM_203486.3	P1	Q9NYJ7-2
DLL3	ENST00000205143.4 linkuse as main transcript	c.534C>G	p.Cys178Trp	missense_variant	4/8	1			Q9NYJ7-1
DLL3	ENST00000600437.1 linkuse as main transcript	n.614C>G		non_coding_transcript_exon_variant	4/6	1
DLL3	ENST00000596614.5 linkuse as main transcript	c.409+2267C>G		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

60750

Hom.:

AF XY:

0.0000279

AC XY:

AN XY:

35812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000428

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1288672

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

634420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000776

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000589

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000155

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.69

T;T

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-8.8

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.73

MutPred

0.68

Gain of MoRF binding (P = 0.0114);Gain of MoRF binding (P = 0.0114);

MVP

0.97

MPC

1.8

ClinPred

0.73

GERP RS

2.6

Varity_R

0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over