dbSNP rs786205519: DLL3:p.Cys379Tyr (chr19-39507081-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.60

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.1136G>A	p.Cys379Tyr	missense_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1	Q9NYJ7-2
DLL3	NM_016941.4 link	c.1136G>A	p.Cys379Tyr	missense_variant	Exon 7 of 8		NP_058637.1	Q9NYJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLL3	ENST00000356433.10 link	c.1136G>A	p.Cys379Tyr	missense_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000205143.4 link	c.1136G>A	p.Cys379Tyr	missense_variant	Exon 7 of 8	1		ENSP00000205143.3	Q9NYJ7-1
DLL3	ENST00000596614.5 link	c.452G>A	p.Cys151Tyr	missense_variant	Exon 4 of 4	2		ENSP00000471688.1	M0R177

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1390804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

Alfa

AF:

0.000224

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive

Pathogenic:1

Nov 08, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided

Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

.;.;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;D;T

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.5

MutationAssessor

Pathogenic

4.6

H;.;H

PrimateAI

Pathogenic

0.97

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over