Variant rs1447189148 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_203486.3(DLL3):c.534C>A(p.Cys178Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,440,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

DLL3
NM_203486.3 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.33

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-39502939-C-A is Pathogenic according to our data. Variant chr19-39502939-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3 linkuse as main transcript	c.534C>A	p.Cys178Ter	stop_gained	4/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4 linkuse as main transcript	c.534C>A	p.Cys178Ter	stop_gained	4/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10 linkuse as main transcript	c.534C>A	p.Cys178Ter	stop_gained	4/9	2	NM_203486.3	ENSP00000348810	P1	Q9NYJ7-2
DLL3	ENST00000205143.4 linkuse as main transcript	c.534C>A	p.Cys178Ter	stop_gained	4/8	1		ENSP00000205143		Q9NYJ7-1
DLL3	ENST00000600437.1 linkuse as main transcript	n.614C>A		non_coding_transcript_exon_variant	4/6	1
DLL3	ENST00000596614.5 linkuse as main transcript	c.409+2267C>A		intron_variant		2		ENSP00000471688

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000310

AC:

AN:

1288672

Hom.:

Cov.:

AF XY:

0.00000630

AC XY:

AN XY:

634420

show subpopulations

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:

0.00000290

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jun 23, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.43

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;A

Vest4

0.68

GERP RS

2.6

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