rs1555393172

Positions:

• chr15-40936658-TCGACGGCCGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_019074.4(DLL4):​c.1679_1689del​(p.Pro560GlnfsTer23) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLL4 NM_019074.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.11

Genes affected

DLL4 (HGNC:2910): (delta like canonical Notch ligand 4) This gene is a homolog of the Drosophila delta gene. The delta gene family encodes Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. [provided by RefSeq, Jul 2008]

ACMG classification

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 15-40936658-TCGACGGCCGGA-T is Pathogenic according to our data. Variant chr15-40936658-TCGACGGCCGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520578.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL4	NM_019074.4	c.1679_1689del	p.Pro560GlnfsTer23	frameshift_variant	9/11	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.1679_1689del	p.Pro560GlnfsTer23	frameshift_variant	9/11	1	NM_019074.4	ENSP00000249749	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2014

The c.1679_1689delCGGACGACGGC (p.P560QFS*23) alteration, located in exon 9 (coding exon 9) of the DLL4 gene, consists of a deletion of 11 nucleotides from position 1679 to 1689, causing a translational frameshift with a predicted alternate stop codon after 23 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on the available evidence, this alteration is classified as likely pathogenic. -

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: rs1555393172; hg19: chr15-41228856;