rs1110627

Positions:

• chr19-39504071-T-A
• chr19-39504071-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203486.3(DLL3):​c.653T>A​(p.Leu218Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L218P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DLL3 NM_203486.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002864
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13579923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3	c.653T>A	p.Leu218Gln	missense_variant, splice_region_variant	5/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.653T>A	p.Leu218Gln	missense_variant, splice_region_variant	5/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.653T>A	p.Leu218Gln	missense_variant, splice_region_variant	5/9	2	NM_203486.3	ENSP00000348810	P1
DLL3	ENST00000205143.4	c.653T>A	p.Leu218Gln	missense_variant, splice_region_variant	5/8	1		ENSP00000205143
DLL3	ENST00000600437.1	n.733T>A		splice_region_variant, non_coding_transcript_exon_variant	5/6	1
DLL3	ENST00000596614.5	c.410-2968T>A		intron_variant		2		ENSP00000471688

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460660 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 726692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	10
DANN	Benign	0.53
DEOGEN2	Benign	0.22	.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.87
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.29	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.22
Sift	Benign	0.13	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.044	.;B
Vest4		0.21
MutPred		0.25		Gain of catalytic residue at L218 (P = 0.1159);Gain of catalytic residue at L218 (P = 0.1159);
MVP		0.91
MPC		0.65
ClinPred		0.14	T
GERP RS		0.83
Varity_R		0.062

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		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: rs1110627; hg19: chr19-39994711;