19-39499220-A-G

Position:

• chr19-39499220-A-G

Variant summary

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

The NM_203486.3(DLL3):​c.98A>G​(p.Gln33Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000709 in 1,410,054 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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 (HGNC:):

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	Protein	UniProt
DLL3	NM_203486.3	c.98A>G	p.Gln33Arg	missense_variant	2/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.98A>G	p.Gln33Arg	missense_variant	2/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.98A>G	p.Gln33Arg	missense_variant	2/9	2	NM_203486.3	ENSP00000348810.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410054 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 698638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.98A>G (p.Q33R) alteration is located in exon 2 (coding exon 2) of the DLL3 gene. This alteration results from a A to G substitution at nucleotide position 98, causing the glutamine (Q) at amino acid position 33 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;.;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.094	T;.;T
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.90	.;.;P
Vest4		0.45
MutPred		0.47		Gain of phosphorylation at S36 (P = 0.0623);Gain of phosphorylation at S36 (P = 0.0623);Gain of phosphorylation at S36 (P = 0.0623);
MVP		0.96
MPC		1.1
ClinPred		0.42	T
GERP RS		3.1
Varity_R		0.13

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: rs1343166766; hg19: chr19-39989860;