rs191149379

Positions:

• chr19-39507507-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

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 Benign. Variant got -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. Variant chr19-39507507-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.1562C>T	p.Ser521Phe	missense_variant	7/9	2	NM_203486.3	ENSP00000348810	P1
DLL3	ENST00000205143.4	c.1562C>T	p.Ser521Phe	missense_variant	7/8	1		ENSP00000205143

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

GnomAD3 exomes AF: 0.00749 AC: 1592 AN: 212480 Hom.: 24 AF XY: 0.00713 AC XY: 838 AN XY: 117482

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 SAS exome AF: 0.00126

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

Gnomad4 AFR exome AF: 0.000392

Gnomad4 AMR exome AF: 0.000658

Gnomad4 ASJ exome AF: 0.00116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.0534

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00499

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

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0511

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00284

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	DLL3: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2018	- -

Spondylocostal dysostosis 1, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 05, 2022	- -
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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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
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
MutationTaster	Benign	1.0	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs191149379; hg19: chr19-39998147;