Genetic Variant DLL1:c.670+51G>A (chr6-170288188-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_005618.4(DLL1):c.670+51G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,612,078 control chromosomes in the GnomAD database, including 267,649 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.51 ( 21214 hom., cov: 33)

Exomes 𝑓: 0.57 ( 246435 hom. )

Consequence

DLL1
NM_005618.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.330

Publications

9 publications found

Variant links:

Genes affected

DLL1 (HGNC:2908): (delta like canonical Notch ligand 1) DLL1 is a human homolog of the Notch Delta ligand and is a member of the delta/serrate/jagged family. It plays a role in mediating cell fate decisions during hematopoiesis. It may play a role in cell-to-cell communication. [provided by RefSeq, Jul 2008]

DLL1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DLL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 6-170288188-C-T is Benign according to our data. Variant chr6-170288188-C-T is described in ClinVar as Benign. ClinVar VariationId is 1253770.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL1	NM_005618.4 link	c.670+51G>A		intron_variant	Intron 4 of 10	ENST00000366756.4	NP_005609.3	O00548-1A0A384P5C6
DLL1	XM_005266934.5 link	c.670+51G>A		intron_variant	Intron 4 of 10		XP_005266991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL1	ENST00000366756.4 link	c.670+51G>A		intron_variant	Intron 4 of 10	1	NM_005618.4	ENSP00000355718.3		O00548-1

Frequencies

GnomAD3 genomes

AF:

0.515

AC:

78259

AN:

151970

Hom.:

21203

Cov.:

show subpopulations

Gnomad AFR

AF:

0.412

Gnomad AMI

AF:

0.623

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.593

Gnomad EAS

AF:

0.0738

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.551

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.598

Gnomad OTH

AF:

0.529

GnomAD2 exomes

AF:

0.511

AC:

126531

AN:

247400

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.404

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.583

Gnomad EAS exome

AF:

0.0669

Gnomad FIN exome

AF:

0.531

Gnomad NFE exome

AF:

0.601

Gnomad OTH exome

AF:

0.555

GnomAD4 exome

AF:

0.572

AC:

834642

AN:

1459990

Hom.:

246435

Cov.:

AF XY:

0.570

AC XY:

413903

AN XY:

726290

show subpopulations

African (AFR)

AF:

0.411

AC:

13742

AN:

33454

American (AMR)

AF:

0.514

AC:

22937

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.582

AC:

15211

AN:

26114

East Asian (EAS)

AF:

0.0553

AC:

2193

AN:

39682

South Asian (SAS)

AF:

0.470

AC:

40467

AN:

86182

European-Finnish (FIN)

AF:

0.534

AC:

27960

AN:

52350

Middle Eastern (MID)

AF:

0.620

AC:

3553

AN:

5730

European-Non Finnish (NFE)

AF:

0.608

AC:

675306

AN:

1111538

Other (OTH)

AF:

0.551

AC:

33273

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

18923

37845

56768

75690

94613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18016

36032

54048

72064

90080

<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:

0.515

AC:

78307

AN:

152088

Hom.:

21214

Cov.:

AF XY:

0.510

AC XY:

37911

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.412

AC:

17097

AN:

41474

American (AMR)

AF:

0.543

AC:

8307

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

2058

AN:

3472

East Asian (EAS)

AF:

0.0746

AC:

385

AN:

5162

South Asian (SAS)

AF:

0.448

AC:

2158

AN:

4822

European-Finnish (FIN)

AF:

0.551

AC:

5840

AN:

10590

Middle Eastern (MID)

AF:

0.575

AC:

169

AN:

294

European-Non Finnish (NFE)

AF:

0.598

AC:

40618

AN:

67952

Other (OTH)

AF:

0.525

AC:

1107

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1896

3792

5689

7585

9481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.567

Hom.:

7404

Bravo

AF:

0.509

Asia WGS

AF:

0.253

AC:

885

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 11, 2018

GeneDx

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

-0.84

CADD

Benign

1.1

(source)

DANN

Benign

0.87

PhyloP100

-0.33

Mutation Taster

=100/0

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