19-39502939-C-T

Variant names:

• chr19-39502939-C-T
• rs1447189148
• NM_203486.3:c.534C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_203486.3(DLL3):​c.534C>T​(p.Cys178Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,288,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• 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_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=2.33 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3	c.534C>T	p.Cys178Cys	synonymous_variant	Exon 4 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.534C>T	p.Cys178Cys	synonymous_variant	Exon 4 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.534C>T	p.Cys178Cys	synonymous_variant	Exon 4 of 9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.534C>T	p.Cys178Cys	synonymous_variant	Exon 4 of 8	1		ENSP00000205143.3
DLL3	ENST00000600437.1	n.614C>T		non_coding_transcript_exon_variant	Exon 4 of 6	1
DLL3	ENST00000596614.5	c.409+2267C>T		intron_variant	Intron 3 of 3	2		ENSP00000471688.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000233 AC: 3 AN: 1288668 Hom.: 0 Cov.: 36 AF XY: 0.00000158 AC XY: 1 AN XY: 634416

African (AFR) AF: 0.00 AC: 0 AN: 25770

American (AMR) AF: 0.0000479 AC: 1 AN: 20860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21762

East Asian (EAS) AF: 0.0000356 AC: 1 AN: 28064

South Asian (SAS) AF: 0.00 AC: 0 AN: 67922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035216

Other (OTH) AF: 0.0000188 AC: 1 AN: 53122

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1447189148; hg19: chr19-39993579;