19-39502951-C-G

Position:

• chr19-39502951-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203486.3(DLL3):​c.546C>G​(p.Ala182Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,451,786 control chromosomes in the GnomAD database, including 75,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6461 hom., cov: 33)
  • Exomes 𝑓: 0.32 (69534 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0910

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-39502951-C-G is Benign according to our data. Variant chr19-39502951-C-G is described in ClinVar as [Benign]. Clinvar id is 260780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-39502951-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.091 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3	c.546C>G	p.Ala182Ala	synonymous_variant	4/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.546C>G	p.Ala182Ala	synonymous_variant	4/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.546C>G	p.Ala182Ala	synonymous_variant	4/9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.546C>G	p.Ala182Ala	synonymous_variant	4/8	1		ENSP00000205143.3
DLL3	ENST00000600437.1	n.626C>G		non_coding_transcript_exon_variant	4/6	1
DLL3	ENST00000596614.5	c.409+2279C>G		intron_variant		2		ENSP00000471688.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42702 AN: 151790 Hom.: 6462 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.299

GnomAD3 exomes AF: 0.297 AC: 20055 AN: 67630 Hom.: 3271 AF XY: 0.301 AC XY: 11852 AN XY: 39396

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.0793

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.323 AC: 419378 AN: 1299888 Hom.: 69534 Cov.: 37 AF XY: 0.324 AC XY: 207298 AN XY: 640080

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.286

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.326

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.312

GnomAD4 genome AF: 0.281 AC: 42699 AN: 151898 Hom.: 6461 Cov.: 33 AF XY: 0.285 AC XY: 21182 AN XY: 74238

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.289

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.295

Alfa AF: 0.192 Hom.: 455

Bravo AF: 0.267

Asia WGS AF: 0.226 AC: 781 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spondylocostal dysostosis 1, autosomal recessive Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Syndactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.1
DANN	Benign	0.60

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: rs8106337; hg19: chr19-39993591; COSMIC: COSV52696025; COSMIC: COSV52696025;