Genetic Variant DLL3:p.Pro437ThrfsTer117 (chr19-39507229-G-GCGCGCGGACCCGTGCGC) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_203486.3(DLL3):c.1291_1307dupGACCCGTGCGCCGCGCG(p.Pro437ThrfsTer117) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000801 in 1,372,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

DLL3
NM_203486.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.27

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-39507229-G-GCGCGCGGACCCGTGCGC is Pathogenic according to our data. Variant chr19-39507229-G-GCGCGCGGACCCGTGCGC is described in ClinVar as [Pathogenic]. Clinvar id is 6831.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.1291_1307dupGACCCGTGCGCCGCGCG	p.Pro437ThrfsTer117	frameshift_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1	Q9NYJ7-2
DLL3	NM_016941.4 link	c.1291_1307dupGACCCGTGCGCCGCGCG	p.Pro437ThrfsTer117	frameshift_variant	Exon 7 of 8		NP_058637.1	Q9NYJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLL3	ENST00000356433.10 link	c.1291_1307dupGACCCGTGCGCCGCGCG	p.Pro437ThrfsTer117	frameshift_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000205143.4 link	c.1291_1307dupGACCCGTGCGCCGCGCG	p.Pro437ThrfsTer117	frameshift_variant	Exon 7 of 8	1		ENSP00000205143.3	Q9NYJ7-1
DLL3	ENST00000596614.5 link	c.607_623dupGACCCGTGCGCCGCGCG	p.Pro209ThrfsTer17	frameshift_variant	Exon 4 of 4	2		ENSP00000471688.1	M0R177

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150892

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:

0.0000296

Gnomad OTH

AF:

0.000482

GnomAD4 exome

AF:

0.00000655

AC:

AN:

1221980

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

598974

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000103

Gnomad4 NFE exome

AF:

0.00000498

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73696

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:

0.0000296

Gnomad4 OTH

AF:

0.000482

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive

Pathogenic:1

Jul 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DLL3: PVS1, PM3:Strong, PM2, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

19-39507229-GCGCGCGGACCCGTGCGC-GCGCGCGGACCCGTGCGCCGCGCGGACCCGTGCGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over