rs191149379

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_203486.3(DLL3):c.1562C>T(p.Ser521Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,599,320 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 88 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.322

Publications

0 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=0.0028181076).

BP6

Variant 19-39507507-C-T is Benign according to our data. Variant chr19-39507507-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00629 (958/152322) while in subpopulation NFE AF = 0.00526 (358/68028). AF 95% confidence interval is 0.00481. There are 12 homozygotes in GnomAd4. There are 616 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.1562C>T	p.Ser521Phe	missense	Exon 7 of 9	NP_982353.1
	DLL3	NM_016941.4		c.1562C>T	p.Ser521Phe	missense	Exon 7 of 8	NP_058637.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DLL3	ENST00000356433.10	TSL:2 MANE Select	c.1562C>T	p.Ser521Phe	missense	Exon 7 of 9	ENSP00000348810.4
DLL3	ENST00000205143.4	TSL:1	c.1562C>T	p.Ser521Phe	missense	Exon 7 of 8	ENSP00000205143.3
DLL3	ENST00000596614.5	TSL:2	c.*218C>T		downstream_gene	N/A	ENSP00000471688.1

Frequencies

GnomAD3 genomes

AF:

0.00629

AC:

958

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0511

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00526

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00749

AC:

1592

AN:

212480

AF XY:

0.00713

show subpopulations

Gnomad AFR exome

AF:

0.000174

Gnomad AMR exome

AF:

0.000699

Gnomad ASJ exome

AF:

0.00118

Gnomad EAS exome

AF:

0.0000631

Gnomad FIN exome

AF:

0.0544

Gnomad NFE exome

AF:

0.00511

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00537

AC:

7764

AN:

1446998

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

3776

AN XY:

718758

show subpopulations

African (AFR)

AF:

0.000392

AC:

AN:

33126

American (AMR)

AF:

0.000658

AC:

AN:

42556

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

25782

East Asian (EAS)

AF:

0.00

AC:

AN:

38748

South Asian (SAS)

AF:

0.00146

AC:

123

AN:

84100

European-Finnish (FIN)

AF:

0.0534

AC:

2726

AN:

51050

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00411

AC:

4542

AN:

1106124

Other (OTH)

AF:

0.00499

AC:

298

AN:

59760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

520

1040

1560

2080

2600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00629

AC:

958

AN:

152322

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

616

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41572

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00186

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0511

AC:

543

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00526

AC:

358

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00508

Hom.:

Bravo

AF:

0.00230

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00255

AC:

ExAC

AF:

0.00598

AC:

711

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Spondylocostal dysostosis 1, autosomal recessive (2)

not specified (1)

Syndactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.30

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

PhyloP100

0.32

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Benign

0.10

Sift4G

Benign

0.15

Polyphen

0.044

Vest4

0.15

MVP

0.72

MPC

0.66

ClinPred

0.023

GERP RS

-1.1

Varity_R

0.084

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over