19-39505387-C-T

Variant names:

• chr19-39505387-C-T
• rs2304214
• NM_203486.3:c.1029C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016941.4(DLL3):​c.1029C>T​(p.Pro343Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,613,884 control chromosomes in the GnomAD database, including 84,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6464 hom., cov: 31)
  • Exomes 𝑓: 0.32 (78330 hom.)
• Consequence: DLL3 NM_016941.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.75
• Publications: 28 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-39505387-C-T is Benign according to our data. Variant chr19-39505387-C-T is described in ClinVar as Benign. ClinVar VariationId is 260772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• 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_016941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.1029C>T	p.Pro343Pro	synonymous	Exon 6 of 9	NP_982353.1
	DLL3	NM_016941.4		c.1029C>T	p.Pro343Pro	synonymous	Exon 6 of 8	NP_058637.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.1029C>T	p.Pro343Pro	synonymous	Exon 6 of 9	ENSP00000348810.4
	DLL3	ENST00000205143.4	TSL:1	c.1029C>T	p.Pro343Pro	synonymous	Exon 6 of 8	ENSP00000205143.3
	DLL3	ENST00000600437.1	TSL:1	n.1109C>T		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42755 AN: 151910 Hom.: 6464 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.306 AC: 76913 AN: 251434 AF XY: 0.312

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.323 AC: 472793 AN: 1461856 Hom.: 78330 Cov.: 55 AF XY: 0.325 AC XY: 236487 AN XY: 727234

African (AFR) AF: 0.167 AC: 5596 AN: 33480

American (AMR) AF: 0.306 AC: 13685 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7645 AN: 26136

East Asian (EAS) AF: 0.113 AC: 4499 AN: 39700

South Asian (SAS) AF: 0.330 AC: 28472 AN: 86258

European-Finnish (FIN) AF: 0.390 AC: 20810 AN: 53410

Middle Eastern (MID) AF: 0.383 AC: 2207 AN: 5768

European-Non Finnish (NFE) AF: 0.334 AC: 370856 AN: 1111990

Other (OTH) AF: 0.315 AC: 19023 AN: 60394

GnomAD4 genome AF: 0.281 AC: 42756 AN: 152028 Hom.: 6464 Cov.: 31 AF XY: 0.285 AC XY: 21186 AN XY: 74308

African (AFR) AF: 0.172 AC: 7134 AN: 41468

American (AMR) AF: 0.288 AC: 4392 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1018 AN: 3470

East Asian (EAS) AF: 0.125 AC: 647 AN: 5182

South Asian (SAS) AF: 0.340 AC: 1639 AN: 4824

European-Finnish (FIN) AF: 0.383 AC: 4050 AN: 10570

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22853 AN: 67928

Other (OTH) AF: 0.295 AC: 622 AN: 2110

Alfa AF: 0.317 Hom.: 15597

Bravo AF: 0.267

Asia WGS AF: 0.226 AC: 786 AN: 3478

EpiCase AF: 0.330

EpiControl AF: 0.332

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.8
DANN	Benign	0.74
PhyloP100		-2.7
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: rs2304214; hg19: chr19-39996027; COSMIC: COSV52694293;