rs8107127

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.515T>G(p.Phe172Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,441,728 control chromosomes in the GnomAD database, including 75,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6867 hom., cov: 32)

Exomes 𝑓: 0.32 ( 69010 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.06

Publications

18 publications found

Variant links:

COSMIC-nc: COSV107222231

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=0.0031743944).

BP6

Variant 19-39502920-T-G is Benign according to our data. Variant chr19-39502920-T-G is described in ClinVar as [Benign]. Clinvar id is 41378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.515T>G	p.Phe172Cys	missense_variant	Exon 4 of 9	ENST00000356433.10	NP_982353.1	Q9NYJ7-2
DLL3	NM_016941.4 link	c.515T>G	p.Phe172Cys	missense_variant	Exon 4 of 8		NP_058637.1	Q9NYJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLL3	ENST00000356433.10 link	c.515T>G	p.Phe172Cys	missense_variant	Exon 4 of 9	2	NM_203486.3	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000205143.4 link	c.515T>G	p.Phe172Cys	missense_variant	Exon 4 of 8	1		ENSP00000205143.3	Q9NYJ7-1
DLL3	ENST00000600437.1 link	n.595T>G		non_coding_transcript_exon_variant	Exon 4 of 6	1
DLL3	ENST00000596614.5 link	c.409+2248T>G		intron_variant	Intron 3 of 3	2		ENSP00000471688.1	M0R177

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

44968

AN:

151694

Hom.:

6865

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.306

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.293

Gnomad EAS

AF:

0.125

Gnomad SAS

AF:

0.342

Gnomad FIN

AF:

0.382

Gnomad MID

AF:

0.417

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.312

GnomAD2 exomes

AF:

0.286

AC:

17935

AN:

62816

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.262

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.0758

Gnomad FIN exome

AF:

0.370

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.323

AC:

416975

AN:

1289922

Hom.:

69010

Cov.:

AF XY:

0.324

AC XY:

205878

AN XY:

634828

show subpopulations

African (AFR)

AF:

0.215

AC:

5566

AN:

25884

American (AMR)

AF:

0.279

AC:

5951

AN:

21318

Ashkenazi Jewish (ASJ)

AF:

0.282

AC:

6149

AN:

21828

East Asian (EAS)

AF:

0.111

AC:

3123

AN:

28100

South Asian (SAS)

AF:

0.323

AC:

21969

AN:

68058

European-Finnish (FIN)

AF:

0.390

AC:

12537

AN:

32118

Middle Eastern (MID)

AF:

0.373

AC:

1402

AN:

3762

European-Non Finnish (NFE)

AF:

0.332

AC:

343527

AN:

1035646

Other (OTH)

AF:

0.315

AC:

16751

AN:

53208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

16602

33205

49807

66410

83012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11490

22980

34470

45960

57450

<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:

0.296

AC:

44974

AN:

151806

Hom.:

6867

Cov.:

AF XY:

0.300

AC XY:

22261

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.224

AC:

9280

AN:

41462

American (AMR)

AF:

0.295

AC:

4502

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

1018

AN:

3470

East Asian (EAS)

AF:

0.125

AC:

639

AN:

5132

South Asian (SAS)

AF:

0.344

AC:

1659

AN:

4822

European-Finnish (FIN)

AF:

0.382

AC:

4013

AN:

10514

Middle Eastern (MID)

AF:

0.414

AC:

121

AN:

292

European-Non Finnish (NFE)

AF:

0.336

AC:

22815

AN:

67824

Other (OTH)

AF:

0.307

AC:

650

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1656

3311

4967

6622

8278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

466

932

1398

1864

2330

<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:

0.309

Hom.:

2306

Bravo

AF:

0.284

TwinsUK

AF:

0.321

AC:

1189

ALSPAC

AF:

0.321

AC:

1239

ExAC

AF:

0.184

AC:

7078

Asia WGS

AF:

0.230

AC:

794

AN:

3460

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 22, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Spondylocostal dysostosis 1, autosomal recessive

Benign:3

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Leukodystrophy and acquired microcephaly with or without dystonia;

Benign:1

May 28, 2019

Mendelics

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

Pathogenic

0.93

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Uncertain

0.62

.;D

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

2.1

PrimateAI

Pathogenic

0.96

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Benign

0.28

Sift

Benign

0.045

D;T

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.0080

.;B

Vest4

0.30

MPC

1.9

ClinPred

0.070

GERP RS

2.9

Varity_R

0.15

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over