NM_203486.3:c.352-18C>G

Variant names:

• chr19-39500597-C-G
• rs2304223
• NM_203486.3:c.352-18C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203486.3(DLL3):​c.352-18C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,605,918 control chromosomes in the GnomAD database, including 84,600 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6497 hom., cov: 30)
  • Exomes 𝑓: 0.32 (78103 hom.)
• Consequence: DLL3 NM_203486.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0640
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-39500597-C-G is Benign according to our data. Variant chr19-39500597-C-G is described in ClinVar as Benign. ClinVar VariationId is 260778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.352-18C>G		intron	N/A	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.352-18C>G		intron	N/A	NP_058637.1	Q9NYJ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.352-18C>G		intron	N/A	ENSP00000348810.4	Q9NYJ7-2
	DLL3	ENST00000205143.4	TSL:1	c.352-18C>G		intron	N/A	ENSP00000205143.3	Q9NYJ7-1
	DLL3	ENST00000600437.1	TSL:1	n.432-18C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42855 AN: 151854 Hom.: 6498 Cov.: 30

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.309

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.307 AC: 77079 AN: 251454 AF XY: 0.313

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.323 AC: 469227 AN: 1453946 Hom.: 78103 Cov.: 31 AF XY: 0.325 AC XY: 234910 AN XY: 723654

African (AFR) AF: 0.168 AC: 5587 AN: 33352

American (AMR) AF: 0.307 AC: 13726 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7609 AN: 26062

East Asian (EAS) AF: 0.113 AC: 4478 AN: 39636

South Asian (SAS) AF: 0.333 AC: 28660 AN: 86112

European-Finnish (FIN) AF: 0.390 AC: 20769 AN: 53266

Middle Eastern (MID) AF: 0.383 AC: 2200 AN: 5750

European-Non Finnish (NFE) AF: 0.332 AC: 367317 AN: 1104998

Other (OTH) AF: 0.314 AC: 18881 AN: 60086

GnomAD4 genome AF: 0.282 AC: 42855 AN: 151972 Hom.: 6497 Cov.: 30 AF XY: 0.286 AC XY: 21250 AN XY: 74284

African (AFR) AF: 0.174 AC: 7211 AN: 41476

American (AMR) AF: 0.288 AC: 4395 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1018 AN: 3472

East Asian (EAS) AF: 0.125 AC: 645 AN: 5174

South Asian (SAS) AF: 0.345 AC: 1659 AN: 4814

European-Finnish (FIN) AF: 0.385 AC: 4056 AN: 10548

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22853 AN: 67942

Other (OTH) AF: 0.293 AC: 616 AN: 2104

Alfa AF: 0.252 Hom.: 962

Bravo AF: 0.267

Asia WGS AF: 0.227 AC: 790 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Spondylocostal dysostosis 1, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.4
DANN	Benign	0.78
PhyloP100		0.064
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304223; hg19: chr19-39991237; COSMIC: COSV52694435; COSMIC: COSV52694435;