rs14635

Positions:

• chr19-39507492-G-T

Variant summary

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

The NM_203486.3(DLL3):​c.1547G>T​(p.Arg516Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL3	NM_203486.3	c.1547G>T	p.Arg516Leu	missense_variant	7/9	ENST00000356433.10
DLL3	NM_016941.4	c.1547G>T	p.Arg516Leu	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL3	ENST00000356433.10	c.1547G>T	p.Arg516Leu	missense_variant	7/9	2	NM_203486.3	P1
DLL3	ENST00000205143.4	c.1547G>T	p.Arg516Leu	missense_variant	7/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.58	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.45
Sift	Benign	0.095	T;T
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	.;D
Vest4		0.38
MutPred		0.53		Loss of MoRF binding (P = 0.0258);Loss of MoRF binding (P = 0.0258);
MVP		0.93
MPC		1.7
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs14635; hg19: chr19-39998132;