6-170282680-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005618.4(DLL1):​c.*194C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000303 in 660,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: DLL1 NM_005618.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000303 AC: 2 AN: 660000 Hom.: 0 Cov.: 9 AF XY: 0.00000574 AC XY: 2 AN XY: 348476

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17674

American (AMR) AF: 0.00 AC: 0 AN: 33782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17832

East Asian (EAS) AF: 0.00 AC: 0 AN: 34928

South Asian (SAS) AF: 0.0000165 AC: 1 AN: 60640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2444

European-Non Finnish (NFE) AF: 0.00000240 AC: 1 AN: 416816

Other (OTH) AF: 0.00 AC: 0 AN: 33624

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.2
DANN	Benign	0.75
PhyloP100		1.7

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;