rs786205519

Positions:

• chr19-39507081-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_203486.3(DLL3):​c.1136G>A​(p.Cys379Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.60

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 19-39507081-G-A is Pathogenic according to our data. Variant chr19-39507081-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-39507081-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3	c.1136G>A	p.Cys379Tyr	missense_variant	7/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.1136G>A	p.Cys379Tyr	missense_variant	7/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.1136G>A	p.Cys379Tyr	missense_variant	7/9	2	NM_203486.3	ENSP00000348810	P1
DLL3	ENST00000205143.4	c.1136G>A	p.Cys379Tyr	missense_variant	7/8	1		ENSP00000205143
DLL3	ENST00000596614.5	c.452G>A	p.Cys151Tyr	missense_variant	4/4	2		ENSP00000471688

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1390804 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 687364

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 32

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 08, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;.;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;D;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.5	D
MutationAssessor	Pathogenic	4.6	H;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-8.0	D;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.92
MutPred		0.87		Loss of disorder (P = 0.0377);.;Loss of disorder (P = 0.0377);
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98

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: rs786205519; hg19: chr19-39997721;