6-170282690-G-A

Variant names:

• chr6-170282690-G-A
• rs17860720
• NM_005618.4:c.*184C>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_005618.4(DLL1):​c.*184C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00701 in 937,340 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0073 (47 hom.)
• Consequence: DLL1 NM_005618.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.413
• Publications: 1 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-170282690-G-A is Benign according to our data. Variant chr6-170282690-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1254894.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 = 0.00552 (841/152388) while in subpopulation NFE AF = 0.00775 (527/68038). AF 95% confidence interval is 0.0072. There are 1 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 841 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL1	NM_005618.4	c.*184C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000366756.4	NP_005609.3
DLL1	XM_005266934.5	c.*184C>T		3_prime_UTR_variant	Exon 11 of 11		XP_005266991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL1	ENST00000366756.4	c.*184C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_005618.4	ENSP00000355718.3

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152270 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00774

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00729 AC: 5726 AN: 784952 Hom.: 47 Cov.: 11 AF XY: 0.00715 AC XY: 2922 AN XY: 408398

African (AFR) AF: 0.00134 AC: 27 AN: 20124

American (AMR) AF: 0.00507 AC: 185 AN: 36466

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 62 AN: 19276

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35862

South Asian (SAS) AF: 0.00413 AC: 269 AN: 65124

European-Finnish (FIN) AF: 0.0154 AC: 690 AN: 44774

Middle Eastern (MID) AF: 0.00220 AC: 6 AN: 2722

European-Non Finnish (NFE) AF: 0.00798 AC: 4174 AN: 522776

Other (OTH) AF: 0.00825 AC: 312 AN: 37828

GnomAD4 genome AF: 0.00552 AC: 841 AN: 152388 Hom.: 1 Cov.: 34 AF XY: 0.00556 AC XY: 414 AN XY: 74516

African (AFR) AF: 0.00130 AC: 54 AN: 41606

American (AMR) AF: 0.00385 AC: 59 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4834

European-Finnish (FIN) AF: 0.0131 AC: 139 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00775 AC: 527 AN: 68038

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00693 Hom.: 0

Bravo AF: 0.00453

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 06, 2021

GeneDx

Significance: Likely 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	-0.91
CADD	Benign	3.6
DANN	Benign	0.87
PhyloP100		-0.41
Mutation Taster		=100/0	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: rs17860720; hg19: chr6-170591778;