chr6-170282680-G-A

Variant names:

• chr6-170282680-G-A
• rs41269629
• NM_005618.4:c.*194C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005618.4(DLL1):​c.*194C>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 0.0219 in 812,262 control chromosomes in the GnomAD database, including 473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (83 hom., cov: 34)
  • Exomes 𝑓: 0.022 (390 hom.)
• Consequence: DLL1 NM_005618.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 6-170282680-G-A is Benign according to our data. Variant chr6-170282680-G-A is described in ClinVar as Benign. ClinVar VariationId is 1268928.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0198 (3024/152368) while in subpopulation NFE AF = 0.0224 (1524/68032). AF 95% confidence interval is 0.0215. There are 83 homozygotes in GnomAd4. There are 1739 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3024 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL1	NM_005618.4	c.*194C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000366756.4	NP_005609.3
DLL1	XM_005266934.5	c.*194C>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.*194C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_005618.4	ENSP00000355718.3

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3022 AN: 152250 Hom.: 83 Cov.: 34

Gnomad AFR AF: 0.00366

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0224

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0223 AC: 14746 AN: 659894 Hom.: 390 Cov.: 9 AF XY: 0.0215 AC XY: 7475 AN XY: 348426

African (AFR) AF: 0.00368 AC: 65 AN: 17672

American (AMR) AF: 0.00536 AC: 181 AN: 33782

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 183 AN: 17832

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34928

South Asian (SAS) AF: 0.00361 AC: 219 AN: 60640

European-Finnish (FIN) AF: 0.110 AC: 4638 AN: 42226

Middle Eastern (MID) AF: 0.0156 AC: 38 AN: 2442

European-Non Finnish (NFE) AF: 0.0210 AC: 8748 AN: 416748

Other (OTH) AF: 0.0200 AC: 673 AN: 33624

GnomAD4 genome AF: 0.0198 AC: 3024 AN: 152368 Hom.: 83 Cov.: 34 AF XY: 0.0233 AC XY: 1739 AN XY: 74502

African (AFR) AF: 0.00368 AC: 153 AN: 41596

American (AMR) AF: 0.00647 AC: 99 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4832

European-Finnish (FIN) AF: 0.109 AC: 1159 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0224 AC: 1524 AN: 68032

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0263 Hom.: 8

Bravo AF: 0.0108

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2019

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	-0.62
CADD	Benign	7.1
DANN	Benign	0.81
PhyloP100		1.7
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: rs41269629; hg19: chr6-170591768;