rs2278440

Variant names:

• chr19-39502775-C-T
• rs2278440
• NM_203486.3:c.410-40C>T

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.410-40C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,333,112 control chromosomes in the GnomAD database, including 70,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6487 hom., cov: 32)
  • Exomes 𝑓: 0.32 (63932 hom.)
• Consequence: DLL3 NM_203486.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.100
• Publications: 4 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=-0.77).
• BP6: Variant 19-39502775-C-T is Benign according to our data. Variant chr19-39502775-C-T is described in ClinVar as Benign. ClinVar VariationId is 260779.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.410-40C>T		intron	N/A	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.410-40C>T		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.410-40C>T		intron	N/A	ENSP00000348810.4	Q9NYJ7-2
	DLL3	ENST00000205143.4	TSL:1	c.410-40C>T		intron	N/A	ENSP00000205143.3	Q9NYJ7-1
	DLL3	ENST00000600437.1	TSL:1	n.490-40C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42780 AN: 151924 Hom.: 6488 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.298

GnomAD2 exomes AF: 0.294 AC: 12762 AN: 43468 AF XY: 0.305

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.0908

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.325 AC: 383487 AN: 1181072 Hom.: 63932 Cov.: 33 AF XY: 0.327 AC XY: 187066 AN XY: 572138

African (AFR) AF: 0.165 AC: 3954 AN: 23998

American (AMR) AF: 0.293 AC: 3867 AN: 13210

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 4665 AN: 15946

East Asian (EAS) AF: 0.111 AC: 3108 AN: 28092

South Asian (SAS) AF: 0.347 AC: 15070 AN: 43448

European-Finnish (FIN) AF: 0.394 AC: 11112 AN: 28180

Middle Eastern (MID) AF: 0.373 AC: 1206 AN: 3232

European-Non Finnish (NFE) AF: 0.333 AC: 325470 AN: 977206

Other (OTH) AF: 0.315 AC: 15035 AN: 47760

GnomAD4 genome AF: 0.281 AC: 42780 AN: 152040 Hom.: 6487 Cov.: 32 AF XY: 0.285 AC XY: 21223 AN XY: 74340

African (AFR) AF: 0.172 AC: 7131 AN: 41504

American (AMR) AF: 0.287 AC: 4392 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1015 AN: 3468

East Asian (EAS) AF: 0.126 AC: 648 AN: 5158

South Asian (SAS) AF: 0.343 AC: 1655 AN: 4820

European-Finnish (FIN) AF: 0.385 AC: 4074 AN: 10576

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.336 AC: 22841 AN: 67906

Other (OTH) AF: 0.294 AC: 622 AN: 2114

Alfa AF: 0.308 Hom.: 989

Bravo AF: 0.267

Asia WGS AF: 0.227 AC: 789 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.8
DANN	Benign	0.89
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2278440; hg19: chr19-39993415;