rs55741253

Positions:

• chr19-39502830-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203486.3(DLL3):​c.425T>A​(p.Leu142Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0767 in 1,421,728 control chromosomes in the GnomAD database, including 4,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (398 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4404 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025883317).
• BP6: Variant 19-39502830-T-A is Benign according to our data. Variant chr19-39502830-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 41377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-39502830-T-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3	c.425T>A	p.Leu142Gln	missense_variant	4/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.425T>A	p.Leu142Gln	missense_variant	4/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.425T>A	p.Leu142Gln	missense_variant	4/9	2	NM_203486.3	ENSP00000348810.4
DLL3	ENST00000205143.4	c.425T>A	p.Leu142Gln	missense_variant	4/8	1		ENSP00000205143.3
DLL3	ENST00000600437.1	n.505T>A		non_coding_transcript_exon_variant	4/6	1
DLL3	ENST00000596614.5	c.409+2158T>A		intron_variant		2		ENSP00000471688.1

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9859 AN: 152010 Hom.: 398 Cov.: 32

Gnomad AFR AF: 0.0675

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0550

GnomAD3 exomes AF: 0.0579 AC: 3980 AN: 68696 Hom.: 156 AF XY: 0.0557 AC XY: 2276 AN XY: 40880

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.0545

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.000928

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0825

Gnomad OTH exome AF: 0.0480

GnomAD4 exome AF: 0.0782 AC: 99239 AN: 1269604 Hom.: 4404 Cov.: 36 AF XY: 0.0756 AC XY: 47260 AN XY: 625458

Gnomad4 AFR exome AF: 0.0632

Gnomad4 AMR exome AF: 0.0464

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.000241

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0539

Gnomad4 NFE exome AF: 0.0881

Gnomad4 OTH exome AF: 0.0653

GnomAD4 genome AF: 0.0648 AC: 9857 AN: 152124 Hom.: 398 Cov.: 32 AF XY: 0.0614 AC XY: 4569 AN XY: 74382

Gnomad4 AFR AF: 0.0673

Gnomad4 AMR AF: 0.0477

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0512

Gnomad4 NFE AF: 0.0801

Gnomad4 OTH AF: 0.0544

Alfa AF: 0.0703 Hom.: 50

Bravo AF: 0.0670

TwinsUK AF: 0.0955 AC: 354

ALSPAC AF: 0.0939 AC: 362

ESP6500AA AF: 0.0526 AC: 134

ESP6500EA AF: 0.0611 AC: 328

ExAC AF: 0.0434 AC: 4668

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Significance: Benign/Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 25, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	0.29
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	.;D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.95	.;P
Vest4		0.68
MPC		1.6
ClinPred		0.023	T
GERP RS		2.4
Varity_R		0.64

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: rs55741253; hg19: chr19-39993470; COSMIC: COSV52694587; COSMIC: COSV52694587;