rs777791545

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-39507229-GCGCGCGGACCCGTGCGC-G
• chr19-39507229-GCGCGCGGACCCGTGCGC-GCGCGCGGACCCGTGCGCCGCGCGGACCCGTGCGC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 1, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift	Exon 7 of 9	NP_982353.1
	DLL3	NM_016941.4		c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift	Exon 7 of 8	NP_058637.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift	Exon 7 of 9	ENSP00000348810.4
	DLL3	ENST00000205143.4	TSL:1	c.1291_1307delGACCCGTGCGCCGCGCG	p.Asp431ProfsTer29	frameshift	Exon 7 of 8	ENSP00000205143.3
	DLL3	ENST00000596614.5	TSL:2	c.607_623delGACCCGTGCGCCGCGCG	p.Asp203ProfsTer12	frameshift	Exon 4 of 4	ENSP00000471688.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000523 AC: 2 AN: 38208 AF XY: 0.0000828

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 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

African (AFR) AF: 0.00 AC: 0 AN: 23972

American (AMR) AF: 0.000343 AC: 4 AN: 11660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19088

East Asian (EAS) AF: 0.00 AC: 0 AN: 27204

South Asian (SAS) AF: 0.00 AC: 0 AN: 52754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1004266

Other (OTH) AF: 0.00 AC: 0 AN: 49792

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=34/166	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs777791545; hg19: chr19-39997869;