rs786200899

chr19-39502998-C-CGCGGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_203486.3(DLL3):c.599_603dup(p.Pro202AlafsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000828 in 1,485,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S198S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: DLL3 NM_203486.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.785

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 19-39502998-C-CGCGGT is Pathogenic according to our data. Variant chr19-39502998-C-CGCGGT is described in ClinVar as [Pathogenic]. Clinvar id is 6828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL3	NM_203486.3	c.599_603dup	p.Pro202AlafsTer41	frameshift_variant	4/9	ENST00000356433.10
DLL3	NM_016941.4	c.599_603dup	p.Pro202AlafsTer41	frameshift_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL3	ENST00000356433.10	c.599_603dup	p.Pro202AlafsTer41	frameshift_variant	4/9	2	NM_203486.3	P1
DLL3	ENST00000205143.4	c.599_603dup	p.Pro202AlafsTer41	frameshift_variant	4/8	1
DLL3	ENST00000600437.1	n.679_683dup		non_coding_transcript_exon_variant	4/6	1
DLL3	ENST00000596614.5	c.409+2332_409+2336dup		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000596 AC: 5 AN: 83876 Hom.: 0 AF XY: 0.0000630 AC XY: 3 AN XY: 47600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000120

Gnomad ASJ exome AF: 0.000153

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000649

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000848 AC: 113 AN: 1333034 Hom.: 0 Cov.: 33 AF XY: 0.0000913 AC XY: 60 AN XY: 657036

Gnomad4 AFR exome AF: 0.000333

Gnomad4 AMR exome AF: 0.000210

Gnomad4 ASJ exome AF: 0.0000850

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.0000678

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000804

Gnomad4 OTH exome AF: 0.0000901

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74218

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000194 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2018	Variant summary: DLL3 c.599_603dupGCGGT (p.Pro202AlafsX41) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.1e-05 in 113278 control chromosomes (gnomAD and publications).The variant, c.599_603dupGCGGT, has been reported in the literature in one consanguineous family in multiple homozygotes affected with Spondylocostal dysostosis 1 and in one heterozygote with a milder phenotype (Bulman_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Pro202Alafs*41) in the DLL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DLL3 are known to be pathogenic (PMID: 12746394). This variant is present in population databases (rs750107624, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with spondylocostal dysostosis (PMID: 10742114, 29620724). ClinVar contains an entry for this variant (Variation ID: 6828). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10742114, 29620724, 31589614, 35137400, 14708096, 12746394) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -

Leukodystrophy and acquired microcephaly with or without dystonia; Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786200899; hg19: chr19-39993638;