19-39507252-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_203486.3(DLL3):c.1307G>A(p.Arg436His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,508,872 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R436R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.269

Publications

1 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009253353).

BP6

Variant 19-39507252-G-A is Benign according to our data. Variant chr19-39507252-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00293 (444/151500) while in subpopulation AFR AF = 0.0102 (423/41448). AF 95% confidence interval is 0.0094. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.1307G>A	p.Arg436His	missense	Exon 7 of 9	NP_982353.1
	DLL3	NM_016941.4		c.1307G>A	p.Arg436His	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.1307G>A	p.Arg436His	missense	Exon 7 of 9	ENSP00000348810.4
DLL3	ENST00000205143.4	TSL:1	c.1307G>A	p.Arg436His	missense	Exon 7 of 8	ENSP00000205143.3
DLL3	ENST00000596614.5	TSL:2	c.623G>A	p.Arg208His	missense	Exon 4 of 4	ENSP00000471688.1

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

441

AN:

151392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000527

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:

0.000118

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.000528

AC:

AN:

106144

AF XY:

0.000439

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.000687

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00122

GnomAD4 exome

AF:

0.000368

AC:

500

AN:

1357372

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

236

AN XY:

669746

show subpopulations

African (AFR)

AF:

0.0102

AC:

282

AN:

27694

American (AMR)

AF:

0.000807

AC:

AN:

33468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24112

East Asian (EAS)

AF:

0.00

AC:

AN:

32428

South Asian (SAS)

AF:

0.0000261

AC:

AN:

76586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33336

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5004

European-Non Finnish (NFE)

AF:

0.000130

AC:

139

AN:

1068220

Other (OTH)

AF:

0.000761

AC:

AN:

56524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00293

AC:

444

AN:

151500

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

200

AN XY:

74066

show subpopulations

African (AFR)

AF:

0.0102

AC:

423

AN:

41448

American (AMR)

AF:

0.000526

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67808

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00236

Hom.:

Bravo

AF:

0.00328

ExAC

AF:

0.000254

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 15, 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 22, 2017

GeneDx

Significance:Likely 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.

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Spondylocostal dysostosis 1, autosomal recessive

Benign:1

Jun 11, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.083

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0093

MetaSVM

Benign

-0.32

MutationAssessor

Benign

-0.035

PhyloP100

-0.27

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.68

REVEL

Benign

0.23

Sift

Benign

0.18

Sift4G

Benign

0.092

Polyphen

0.99

Vest4

0.31

MVP

0.95

MPC

1.7

ClinPred

0.038

GERP RS

3.4

Varity_R

0.042

Mutation Taster

=88/12

polymorphism

(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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over