6-170282881-TG-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005618.4(DLL1):c.2167-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,168 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: DLL1 NM_005618.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.812

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 6-170282881-TG-T is Benign according to our data. Variant chr6-170282881-TG-T is described in ClinVar as [Likely_benign]. Clinvar id is 1542633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00114 (174/152314) while in subpopulation NFE AF= 0.00188 (128/68026). AF 95% confidence interval is 0.00162. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL1	NM_005618.4	c.2167-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366756.4
DLL1	XM_005266934.5	c.1570-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL1	ENST00000366756.4	c.2167-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005618.4	P1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00115 AC: 290 AN: 251486 Hom.: 0 AF XY: 0.00121 AC XY: 165 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00123 AC: 1799 AN: 1461854 Hom.: 1 Cov.: 34 AF XY: 0.00128 AC XY: 928 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00140

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74470

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000967

EpiCase AF: 0.00256

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DLL1: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs534959107; hg19: chr6-170591969;