rs2278440

chr19-39502775-C-T

Variant summary

Our verdict is Benign. Variant got -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:3
• Conservation: PhyloP100: 0.100

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL3	NM_203486.3	c.410-40C>T		intron_variant		ENST00000356433.10
DLL3	NM_016941.4	c.410-40C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL3	ENST00000356433.10	c.410-40C>T		intron_variant		2	NM_203486.3	P1
DLL3	ENST00000205143.4	c.410-40C>T		intron_variant		1
DLL3	ENST00000600437.1	n.490-40C>T		intron_variant, non_coding_transcript_variant		1
DLL3	ENST00000596614.5	c.409+2103C>T		intron_variant		2

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

GnomAD3 exomes AF: 0.294 AC: 12762 AN: 43468 Hom.: 2041 AF XY: 0.305 AC XY: 7735 AN XY: 25332

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 SAS exome AF: 0.365

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

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.293

Gnomad4 ASJ exome AF: 0.293

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.315

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

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.294

Alfa AF: 0.314 Hom.: 981

Bravo AF: 0.267

Asia WGS AF: 0.227 AC: 789 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Spondylocostal dysostosis 1, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 19, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.8
Dann	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs2278440; hg19: chr19-39993415;