rs55741253

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.425T>A(p.Leu142Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0767 in 1,421,728 control chromosomes in the GnomAD database, including 4,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 398 hom., cov: 32)

Exomes 𝑓: 0.078 ( 4404 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.82

Publications

8 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: G2P, Labcorp Genetics (formerly Invitae)
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=0.0025883317).

BP6

Variant 19-39502830-T-A is Benign according to our data. Variant chr19-39502830-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.425T>A	p.Leu142Gln	missense	Exon 4 of 9	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.425T>A	p.Leu142Gln	missense	Exon 4 of 8	NP_058637.1	Q9NYJ7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DLL3	ENST00000356433.10	TSL:2 MANE Select	c.425T>A	p.Leu142Gln	missense	Exon 4 of 9	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000205143.4	TSL:1	c.425T>A	p.Leu142Gln	missense	Exon 4 of 8	ENSP00000205143.3	Q9NYJ7-1
DLL3	ENST00000600437.1	TSL:1	n.505T>A		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes

AF:

0.0649

AC:

9859

AN:

152010

Hom.:

398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0675

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0478

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.0512

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0801

Gnomad OTH

AF:

0.0550

GnomAD2 exomes

AF:

0.0579

AC:

3980

AN:

68696

AF XY:

0.0557

show subpopulations

Gnomad AFR exome

AF:

0.0814

Gnomad AMR exome

AF:

0.0545

Gnomad ASJ exome

AF:

0.0209

Gnomad EAS exome

AF:

0.000928

Gnomad FIN exome

AF:

0.0521

Gnomad NFE exome

AF:

0.0825

Gnomad OTH exome

AF:

0.0480

GnomAD4 exome

AF:

0.0782

AC:

99239

AN:

1269604

Hom.:

4404

Cov.:

AF XY:

0.0756

AC XY:

47260

AN XY:

625458

show subpopulations

African (AFR)

AF:

0.0632

AC:

1614

AN:

25556

American (AMR)

AF:

0.0464

AC:

909

AN:

19610

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

393

AN:

19824

East Asian (EAS)

AF:

0.000241

AC:

AN:

29048

South Asian (SAS)

AF:

0.0118

AC:

729

AN:

61782

European-Finnish (FIN)

AF:

0.0539

AC:

1737

AN:

32252

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

3630

European-Non Finnish (NFE)

AF:

0.0881

AC:

90410

AN:

1026030

Other (OTH)

AF:

0.0653

AC:

3386

AN:

51872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

6078

12156

18233

24311

30389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3584

7168

10752

14336

17920

<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:

0.0648

AC:

9857

AN:

152124

Hom.:

398

Cov.:

AF XY:

0.0614

AC XY:

4569

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0673

AC:

2793

AN:

41508

American (AMR)

AF:

0.0477

AC:

729

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3470

East Asian (EAS)

AF:

0.000583

AC:

AN:

5142

South Asian (SAS)

AF:

0.0128

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0512

AC:

543

AN:

10604

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0801

AC:

5445

AN:

67964

Other (OTH)

AF:

0.0544

AC:

115

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

508

1016

1524

2032

2540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0703

Hom.:

Bravo

AF:

0.0670

TwinsUK

AF:

0.0955

AC:

354

ALSPAC

AF:

0.0939

AC:

362

ESP6500AA

AF:

0.0526

AC:

134

ESP6500EA

AF:

0.0611

AC:

328

ExAC

AF:

0.0434

AC:

4668

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Spondylocostal dysostosis 1, autosomal recessive (3)

not provided (2)

Syndactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.77

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0026

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.1

PhyloP100

4.8

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.020

Polyphen

0.95

Vest4

0.68

MPC

1.6

ClinPred

0.023

GERP RS

2.4

Varity_R

0.64

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over