15-40930289-G-C

Variant names:

• chr15-40930289-G-C
• rs12441495
• NM_019074.4:c.336+173G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019074.4(DLL4):​c.336+173G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 841,496 control chromosomes in the GnomAD database, including 5,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (671 hom., cov: 32)
  • Exomes 𝑓: 0.11 (4669 hom.)
• Consequence: DLL4 NM_019074.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.296
• Publications: 4 publications found

Genes affected

DLL4 (HGNC:2910): (delta like canonical Notch ligand 4) This gene is a homolog of the Drosophila delta gene. The delta gene family encodes Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. [provided by RefSeq, Jul 2008]

DLL4 Gene-Disease associations (from GenCC):

• Adams-Oliver syndrome 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Adams-Oliver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• aplasia cutis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 15-40930289-G-C is Benign according to our data. Variant chr15-40930289-G-C is described in ClinVar as Benign. ClinVar VariationId is 1290722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL4	NM_019074.4	c.336+173G>C		intron_variant	Intron 2 of 10	ENST00000249749.7	NP_061947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL4	ENST00000249749.7	c.336+173G>C		intron_variant	Intron 2 of 10	1	NM_019074.4	ENSP00000249749.5
DLL4	ENST00000557876.1	n.838G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0816 AC: 12355 AN: 151470 Hom.: 670 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.0916

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.0909

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.0525

Gnomad FIN AF: 0.0785

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0964

GnomAD4 exome AF: 0.108 AC: 74596 AN: 689906 Hom.: 4669 Cov.: 9 AF XY: 0.107 AC XY: 37467 AN XY: 351774

African (AFR) AF: 0.0196 AC: 333 AN: 16958

American (AMR) AF: 0.0733 AC: 1496 AN: 20402

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 1350 AN: 15378

East Asian (EAS) AF: 0.000279 AC: 9 AN: 32236

South Asian (SAS) AF: 0.0566 AC: 2916 AN: 51496

European-Finnish (FIN) AF: 0.0791 AC: 2439 AN: 30818

Middle Eastern (MID) AF: 0.114 AC: 284 AN: 2488

European-Non Finnish (NFE) AF: 0.128 AC: 62227 AN: 486268

Other (OTH) AF: 0.105 AC: 3542 AN: 33862

GnomAD4 genome AF: 0.0815 AC: 12354 AN: 151590 Hom.: 671 Cov.: 32 AF XY: 0.0783 AC XY: 5797 AN XY: 74032

African (AFR) AF: 0.0232 AC: 956 AN: 41266

American (AMR) AF: 0.0847 AC: 1291 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0909 AC: 315 AN: 3466

East Asian (EAS) AF: 0.00117 AC: 6 AN: 5112

South Asian (SAS) AF: 0.0527 AC: 252 AN: 4778

European-Finnish (FIN) AF: 0.0785 AC: 825 AN: 10516

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8396 AN: 67902

Other (OTH) AF: 0.0950 AC: 200 AN: 2106

Alfa AF: 0.0926 Hom.: 91

Bravo AF: 0.0801

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 08, 2018

GeneDx

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.51
PhyloP100		0.30
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12441495; hg19: chr15-41222487;