chr19-39507492-G-A

Variant names:

• chr19-39507492-G-A
• rs14635
• NM_203486.3:c.1547G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_203486.3(DLL3):​c.1547G>A​(p.Arg516His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,770 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41771758).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.1547G>A	p.Arg516His	missense	Exon 7 of 9	NP_982353.1
	DLL3	NM_016941.4		c.1547G>A	p.Arg516His	missense	Exon 7 of 8	NP_058637.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.1547G>A	p.Arg516His	missense	Exon 7 of 9	ENSP00000348810.4
	DLL3	ENST00000205143.4	TSL:1	c.1547G>A	p.Arg516His	missense	Exon 7 of 8	ENSP00000205143.3
	DLL3	ENST00000596614.5	TSL:2	c.*203G>A		downstream_gene	N/A	ENSP00000471688.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441770 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715606

⚠️ 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: 33012

American (AMR) AF: 0.00 AC: 0 AN: 41670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25702

East Asian (EAS) AF: 0.00 AC: 0 AN: 38422

South Asian (SAS) AF: 0.00 AC: 0 AN: 83656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103584

Other (OTH) AF: 0.00 AC: 0 AN: 59556

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.28
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.50		Loss of MoRF binding (P = 0.0154)
MVP		0.92
MPC		1.7
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.23
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs14635; hg19: chr19-39998132;