19-39502951-C-G

Variant names:

• chr19-39502951-C-G
• rs8106337
• NM_203486.3:c.546C>G

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. A182A) has been classified as Likely 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
• Publications: 8 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: Benign. The variant received -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 VariationId is 260780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.546C>G	p.Ala182Ala	synonymous	Exon 4 of 9	NP_982353.1
	DLL3	NM_016941.4		c.546C>G	p.Ala182Ala	synonymous	Exon 4 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.546C>G	p.Ala182Ala	synonymous	Exon 4 of 9	ENSP00000348810.4
	DLL3	ENST00000205143.4	TSL:1	c.546C>G	p.Ala182Ala	synonymous	Exon 4 of 8	ENSP00000205143.3
	DLL3	ENST00000600437.1	TSL:1	n.626C>G		non_coding_transcript_exon	Exon 4 of 6

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

GnomAD2 exomes AF: 0.297 AC: 20055 AN: 67630 AF XY: 0.301

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 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

African (AFR) AF: 0.163 AC: 4266 AN: 26106

American (AMR) AF: 0.285 AC: 6497 AN: 22794

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 6381 AN: 22312

East Asian (EAS) AF: 0.111 AC: 3149 AN: 28366

South Asian (SAS) AF: 0.326 AC: 22653 AN: 69508

European-Finnish (FIN) AF: 0.392 AC: 12700 AN: 32422

Middle Eastern (MID) AF: 0.371 AC: 1413 AN: 3806

European-Non Finnish (NFE) AF: 0.332 AC: 345569 AN: 1040894

Other (OTH) AF: 0.312 AC: 16750 AN: 53680

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

African (AFR) AF: 0.172 AC: 7120 AN: 41498

American (AMR) AF: 0.289 AC: 4408 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3470

East Asian (EAS) AF: 0.125 AC: 644 AN: 5160

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4824

European-Finnish (FIN) AF: 0.382 AC: 4013 AN: 10504

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.336 AC: 22817 AN: 67858

Other (OTH) AF: 0.295 AC: 623 AN: 2112

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

Mar 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spondylocostal dysostosis 1, autosomal recessive Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Syndactyly Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.1
DANN	Benign	0.60
PhyloP100		-0.091
Mutation Taster		=100/0	polymorphism (auto)

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