rs104894674

Variant names:

• chr19-39507099-G-A
• rs104894674
• NM_203486.3:c.1154G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203486.3(DLL3):​c.1154G>A​(p.Gly385Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,391,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.33

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3	c.1154G>A	p.Gly385Asp	missense_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.1154G>A	p.Gly385Asp	missense_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.1154G>A	p.Gly385Asp	missense_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.1154G>A	p.Gly385Asp	missense_variant	Exon 7 of 8	1		ENSP00000205143.3
DLL3	ENST00000596614.5	c.470G>A	p.Gly157Asp	missense_variant	Exon 4 of 4	2		ENSP00000471688.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1391250 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 687702

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: 0.0000500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive Pathogenic:1

Apr 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Mar 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12791036, 12746394, 14708096, 17041936, 10742114, 36506336, 11377959) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;H
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.80
MutPred		0.97		Loss of catalytic residue at G385 (P = 0.0817);.;Loss of catalytic residue at G385 (P = 0.0817);
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs104894674; hg19: chr19-39997739;