rs111494897

Variant names:

• chr15-40929564-C-G
• rs111494897
• NM_019074.4:c.-105C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-40929564-C-G
• chr15-40929564-C-A
• chr15-40929564-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_019074.4(DLL4):​c.-105C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00495 in 1,061,306 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (49 hom.)
• Consequence: DLL4 NM_019074.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.115
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.78).
• BP6: Variant 15-40929564-C-G is Benign according to our data. Variant chr15-40929564-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1193817.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 = 0.0093 (1416/152332) while in subpopulation AFR AF = 0.0253 (1053/41566). AF 95% confidence interval is 0.0241. There are 20 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1416 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019074.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL4	NM_019074.4	MANE Select	c.-105C>G		5_prime_UTR	Exon 1 of 11	NP_061947.1	Q9NR61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL4	ENST00000249749.7	TSL:1 MANE Select	c.-105C>G		5_prime_UTR	Exon 1 of 11	ENSP00000249749.5	Q9NR61
	DLL4	ENST00000878560.1		c.-105C>G		5_prime_UTR	Exon 1 of 11	ENSP00000548619.1
	DLL4	ENST00000878561.1		c.-105C>G		5_prime_UTR	Exon 1 of 8	ENSP00000548620.1

Frequencies

GnomAD3 genomes AF: 0.00928 AC: 1413 AN: 152214 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0244

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00422 AC: 3840 AN: 908974 Hom.: 49 Cov.: 12 AF XY: 0.00504 AC XY: 2284 AN XY: 453232

African (AFR) AF: 0.0263 AC: 534 AN: 20340

American (AMR) AF: 0.00299 AC: 56 AN: 18712

Ashkenazi Jewish (ASJ) AF: 0.00587 AC: 95 AN: 16180

East Asian (EAS) AF: 0.0000308 AC: 1 AN: 32448

South Asian (SAS) AF: 0.0294 AC: 1627 AN: 55344

European-Finnish (FIN) AF: 0.000163 AC: 5 AN: 30672

Middle Eastern (MID) AF: 0.0150 AC: 43 AN: 2860

European-Non Finnish (NFE) AF: 0.00176 AC: 1214 AN: 691708

Other (OTH) AF: 0.00651 AC: 265 AN: 40710

GnomAD4 genome AF: 0.00930 AC: 1416 AN: 152332 Hom.: 20 Cov.: 33 AF XY: 0.00969 AC XY: 722 AN XY: 74486

African (AFR) AF: 0.0253 AC: 1053 AN: 41566

American (AMR) AF: 0.00353 AC: 54 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 68034

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00944

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		0.12
PromoterAI		0.18	Neutral
Mutation Taster		=300/0	polymorphism

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: rs111494897; hg19: chr15-41221762;