19-39499236-G-A

Variant names:

• chr19-39499236-G-A
• rs1026268120
• NM_203486.3:c.114G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_203486.3(DLL3):​c.114G>A​(p.Gly38Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,668 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. Synonymous variant affecting the same amino acid position (i.e. G38G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.457
• Publications: 0 publications found

Genes affected

DLL3 (HGNC:2909): (delta like canonical Notch ligand 3) This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain. Mutations in this gene cause autosomal recessive spondylocostal dysostosis 1. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DLL3 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 1, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=0.457 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203486.3. 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
	DLL3	NM_203486.3	MANE Select	c.114G>A	p.Gly38Gly	synonymous	Exon 2 of 9	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.114G>A	p.Gly38Gly	synonymous	Exon 2 of 8	NP_058637.1	Q9NYJ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.114G>A	p.Gly38Gly	synonymous	Exon 2 of 9	ENSP00000348810.4	Q9NYJ7-2
	DLL3	ENST00000205143.4	TSL:1	c.114G>A	p.Gly38Gly	synonymous	Exon 2 of 8	ENSP00000205143.3	Q9NYJ7-1
	DLL3	ENST00000600437.1	TSL:1	n.194G>A		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397668 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691336

⚠️ 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: 31894

American (AMR) AF: 0.00 AC: 0 AN: 36696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 36222

South Asian (SAS) AF: 0.00 AC: 0 AN: 80860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4458

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084756

Other (OTH) AF: 0.00 AC: 0 AN: 58154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.7
DANN	Benign	0.83
PhyloP100		0.46
PromoterAI		-0.028	Neutral

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: rs1026268120; hg19: chr19-39989876;