chr19-39498956-A-AC

Position:

• chr19-39498956-A-AC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203486.3(DLL3):​c.-12dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,609,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: DLL3 NM_203486.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3	c.-12dup		5_prime_UTR_variant	1/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.-12dup		5_prime_UTR_variant	1/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.-12dup		5_prime_UTR_variant	1/9	2	NM_203486.3	ENSP00000348810	P1

Frequencies

GnomAD3 genomes AF: 0.0000675 AC: 10 AN: 148054 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000599

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000718 AC: 18 AN: 250802 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135616

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000816

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461618 Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 727118

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000932

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000675 AC: 10 AN: 148054 Hom.: 0 Cov.: 31 AF XY: 0.0000555 AC XY: 4 AN XY: 72096

Gnomad4 AFR AF: 0.0000504

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000599

Gnomad4 SAS AF: 0.00108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Syndactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spondylocostal dysostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs747003629; hg19: chr19-39989596;