NM_203486.3:c.1152G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_203486.3(DLL3):c.1152G>A(p.Ala384Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,543,398 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A384A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 41 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 43 hom. )

Consequence

DLL3
NM_203486.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.565

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 19-39507097-G-A is Benign according to our data. Variant chr19-39507097-G-A is described in ClinVar as Benign. ClinVar VariationId is 260773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.565 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2157/152152) while in subpopulation AFR AF = 0.0487 (2022/41546). AF 95% confidence interval is 0.0469. There are 41 homozygotes in GnomAd4. There are 1021 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3 link	c.1152G>A	p.Ala384Ala	synonymous_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1	Q9NYJ7-2
DLL3	NM_016941.4 link	c.1152G>A	p.Ala384Ala	synonymous_variant	Exon 7 of 8		NP_058637.1	Q9NYJ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLL3	ENST00000356433.10 link	c.1152G>A	p.Ala384Ala	synonymous_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000205143.4 link	c.1152G>A	p.Ala384Ala	synonymous_variant	Exon 7 of 8	1		ENSP00000205143.3	Q9NYJ7-1
DLL3	ENST00000596614.5 link	c.468G>A	p.Ala156Ala	synonymous_variant	Exon 4 of 4	2		ENSP00000471688.1	M0R177

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2153

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00589

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:

0.000309

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00303

AC:

434

AN:

143154

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.0457

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.000122

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000249

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00143

AC:

1993

AN:

1391246

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

848

AN XY:

687682

show subpopulations

African (AFR)

AF:

0.0490

AC:

1563

AN:

31914

American (AMR)

AF:

0.00305

AC:

115

AN:

37682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.00

AC:

AN:

36372

South Asian (SAS)

AF:

0.0000875

AC:

AN:

79976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33904

Middle Eastern (MID)

AF:

0.00274

AC:

AN:

4386

European-Non Finnish (NFE)

AF:

0.000108

AC:

117

AN:

1083854

Other (OTH)

AF:

0.00309

AC:

179

AN:

57992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

109

218

327

436

545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0142

AC:

2157

AN:

152152

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1021

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0487

AC:

2022

AN:

41546

American (AMR)

AF:

0.00589

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67968

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00301

Hom.:

Bravo

AF:

0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 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. -

not provided

Benign:2

Jan 29, 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

- -

Spondylocostal dysostosis 1, autosomal recessive

Benign:1

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.0

(source)

DANN

Benign

0.92

PhyloP100

-0.56

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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