19-39504071-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203486.3(DLL3):c.653T>C(p.Leu218Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,612,248 control chromosomes in the GnomAD database, including 241,474 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L218L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 27535 hom., cov: 32)

Exomes 𝑓: 0.54 ( 213939 hom. )

Consequence

DLL3
NM_203486.3 missense, splice_region

Scores

Splicing: ADA: 0.00005985

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.45

Publications

44 publications found

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 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

DLL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.636819E-6).

BP6

Variant 19-39504071-T-C is Benign according to our data. Variant chr19-39504071-T-C is described in ClinVar as Benign. ClinVar VariationId is 41379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4 link	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	Exon 5 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DLL3	ENST00000356433.10 link	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	Exon 5 of 9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4 link	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	Exon 5 of 8	1		ENSP00000205143.3
DLL3	ENST00000600437.1 link	n.733T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	1
DLL3	ENST00000596614.5 link	c.410-2968T>C		intron_variant	Intron 3 of 3	2		ENSP00000471688.1

Frequencies

GnomAD3 genomes

AF:

0.594

AC:

90304

AN:

151990

Hom.:

27494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.722

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.571

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.655

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.602

GnomAD2 exomes

AF:

0.563

AC:

140647

AN:

249764

AF XY:

0.562

show subpopulations

Gnomad AFR exome

AF:

0.727

Gnomad AMR exome

AF:

0.532

Gnomad ASJ exome

AF:

0.563

Gnomad EAS exome

AF:

0.574

Gnomad FIN exome

AF:

0.651

Gnomad NFE exome

AF:

0.531

Gnomad OTH exome

AF:

0.570

GnomAD4 exome

AF:

0.539

AC:

787206

AN:

1460140

Hom.:

213939

Cov.:

AF XY:

0.541

AC XY:

393009

AN XY:

726490

show subpopulations

African (AFR)

AF:

0.735

AC:

24603

AN:

33470

American (AMR)

AF:

0.531

AC:

23737

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.558

AC:

14592

AN:

26134

East Asian (EAS)

AF:

0.545

AC:

21635

AN:

39700

South Asian (SAS)

AF:

0.563

AC:

48554

AN:

86258

European-Finnish (FIN)

AF:

0.646

AC:

33784

AN:

52272

Middle Eastern (MID)

AF:

0.649

AC:

3743

AN:

5766

European-Non Finnish (NFE)

AF:

0.524

AC:

582619

AN:

1111470

Other (OTH)

AF:

0.562

AC:

33939

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

20904

41808

62712

83616

104520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16744

33488

50232

66976

83720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.594

AC:

90397

AN:

152108

Hom.:

27535

Cov.:

AF XY:

0.599

AC XY:

44566

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.722

AC:

29960

AN:

41482

American (AMR)

AF:

0.524

AC:

8020

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.556

AC:

1927

AN:

3468

East Asian (EAS)

AF:

0.571

AC:

2950

AN:

5168

South Asian (SAS)

AF:

0.582

AC:

2809

AN:

4830

European-Finnish (FIN)

AF:

0.655

AC:

6935

AN:

10594

Middle Eastern (MID)

AF:

0.677

AC:

199

AN:

294

European-Non Finnish (NFE)

AF:

0.529

AC:

35961

AN:

67952

Other (OTH)

AF:

0.604

AC:

1274

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1916

3832

5748

7664

9580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

758

1516

2274

3032

3790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.553

Hom.:

48489

Bravo

AF:

0.588

TwinsUK

AF:

0.508

AC:

1883

ALSPAC

AF:

0.510

AC:

1965

ESP6500AA

AF:

0.720

AC:

3172

ESP6500EA

AF:

0.524

AC:

4503

ExAC

AF:

0.568

AC:

68908

Asia WGS

AF:

0.620

AC:

2156

AN:

3478

EpiCase

AF:

0.530

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Spondylocostal dysostosis 1, autosomal recessive

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Syndactyly

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.037

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.3

(source)

DANN

Benign

0.050

DEOGEN2

Benign

0.20

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-3.1

N;N

PhyloP100

2.4

PrimateAI

Benign

0.47

PROVEAN

Benign

3.4

N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.0

.;B

Vest4

0.054

MPC

0.92

ClinPred

0.0060

GERP RS

0.83

Varity_R

0.039

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000060

dbscSNV1_RF

Benign

0.0080

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over