NM_203486.3:c.1291_1307delGACCCGTGCGCCGCGCG

Variant names:

• chr19-39507229-GCGCGCGGACCCGTGCGC-G
• rs777791545
• NM_203486.3:c.1291_1307delGACCCGTGCGCCGCGCG

Variant summary

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

The NM_203486.3(DLL3):​c.1291_1307delGACCCGTGCGCCGCGCG​(p.Asp431ProfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000327 in 1,221,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. D431D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: DLL3 NM_203486.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

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 19-39507229-GCGCGCGGACCCGTGCGC-G is Pathogenic according to our data. Variant chr19-39507229-GCGCGCGGACCCGTGCGC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift_variant	Exon 7 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift_variant	Exon 7 of 8	1		ENSP00000205143.3
DLL3	ENST00000596614.5	c.607_623delGACCCGTGCGCCGCGCG	p.Asp203ProfsTer12	frameshift_variant	Exon 4 of 4	2		ENSP00000471688.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000523 AC: 2 AN: 38208 Hom.: 0 AF XY: 0.0000828 AC XY: 2 AN XY: 24148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000773

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000327 AC: 4 AN: 1221986 Hom.: 0 AF XY: 0.00000501 AC XY: 3 AN XY: 598980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000343

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

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: rs777791545; hg19: chr19-39997869;