rs786200903

Positions:

• chr19-39507384-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_203486.3(DLL3):​c.1440delG​(p.Pro481fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLL3 NM_203486.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.308

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 11 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 19-39507384-CG-C is Pathogenic according to our data. Variant chr19-39507384-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 6834.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3	c.1440delG	p.Pro481fs	frameshift_variant	7/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.1440delG	p.Pro481fs	frameshift_variant	7/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.1440delG	p.Pro481fs	frameshift_variant	7/9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.1440delG	p.Pro481fs	frameshift_variant	7/8	1		ENSP00000205143.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs786200903; hg19: chr19-39998024;