rs191149379

Variant names:

• chr19-39507507-C-T
• rs191149379
• NM_203486.3:c.1562C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_203486.3(DLL3):​c.1562C>T​(p.Ser521Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00545 in 1,599,320 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (88 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.322
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028181076).
• BP6: Variant 19-39507507-C-T is Benign according to our data. Variant chr19-39507507-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00629 (958/152322) while in subpopulation NFE AF = 0.00526 (358/68028). AF 95% confidence interval is 0.00481. There are 12 homozygotes in GnomAd4. There are 616 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3	c.1562C>T	p.Ser521Phe	missense_variant	Exon 7 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.1562C>T	p.Ser521Phe	missense_variant	Exon 7 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.1562C>T	p.Ser521Phe	missense_variant	Exon 7 of 9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.1562C>T	p.Ser521Phe	missense_variant	Exon 7 of 8	1		ENSP00000205143.3
DLL3	ENST00000596614.5	c.*218C>T		downstream_gene_variant		2		ENSP00000471688.1

Frequencies

GnomAD3 genomes AF: 0.00629 AC: 958 AN: 152204 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0511

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00749 AC: 1592 AN: 212480 AF XY: 0.00713

Gnomad AFR exome AF: 0.000174

Gnomad AMR exome AF: 0.000699

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.0000631

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.00511

Gnomad OTH exome AF: 0.00653

GnomAD4 exome AF: 0.00537 AC: 7764 AN: 1446998 Hom.: 88 Cov.: 31 AF XY: 0.00525 AC XY: 3776 AN XY: 718758

African (AFR) AF: 0.000392 AC: 13 AN: 33126

American (AMR) AF: 0.000658 AC: 28 AN: 42556

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 30 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 38748

South Asian (SAS) AF: 0.00146 AC: 123 AN: 84100

European-Finnish (FIN) AF: 0.0534 AC: 2726 AN: 51050

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.00411 AC: 4542 AN: 1106124

Other (OTH) AF: 0.00499 AC: 298 AN: 59760

GnomAD4 genome AF: 0.00629 AC: 958 AN: 152322 Hom.: 12 Cov.: 32 AF XY: 0.00827 AC XY: 616 AN XY: 74480

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4828

European-Finnish (FIN) AF: 0.0511 AC: 543 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00526 AC: 358 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00508 Hom.: 2

Bravo AF: 0.00230

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00255 AC: 20

ExAC AF: 0.00598 AC: 711

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DLL3: BS2 -

Spondylocostal dysostosis 1, autosomal recessive Benign:2

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. -

Apr 05, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.30	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.37	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		0.32
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.17
Sift	Benign	0.10	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.044	.;B
Vest4		0.15
MVP		0.72
MPC		0.66
ClinPred		0.023	T
GERP RS		-1.1
Varity_R		0.084
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs191149379; hg19: chr19-39998147;