rs8107127

Positions:

• chr19-39502920-T-G

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.515T>G​(p.Phe172Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,441,728 control chromosomes in the GnomAD database, including 75,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6867 hom., cov: 32)
  • Exomes 𝑓: 0.32 (69010 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.06

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=0.0031743944).
• BP6: Variant 19-39502920-T-G is Benign according to our data. Variant chr19-39502920-T-G is described in ClinVar as [Benign]. Clinvar id is 41378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-39502920-T-G is described in Lovd as [Benign].
• 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.515T>G	p.Phe172Cys	missense_variant	4/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.515T>G	p.Phe172Cys	missense_variant	4/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.515T>G	p.Phe172Cys	missense_variant	4/9	2	NM_203486.3	ENSP00000348810	P1
DLL3	ENST00000205143.4	c.515T>G	p.Phe172Cys	missense_variant	4/8	1		ENSP00000205143
DLL3	ENST00000600437.1	n.595T>G		non_coding_transcript_exon_variant	4/6	1
DLL3	ENST00000596614.5	c.409+2248T>G		intron_variant		2		ENSP00000471688

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44968 AN: 151694 Hom.: 6865 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.295

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: 0.312

GnomAD3 exomes AF: 0.286 AC: 17935 AN: 62816 Hom.: 2830 AF XY: 0.290 AC XY: 10638 AN XY: 36714

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.0758

Gnomad SAS exome AF: 0.299

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.323 AC: 416975 AN: 1289922 Hom.: 69010 Cov.: 36 AF XY: 0.324 AC XY: 205878 AN XY: 634828

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.282

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.296 AC: 44974 AN: 151806 Hom.: 6867 Cov.: 32 AF XY: 0.300 AC XY: 22261 AN XY: 74198

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.295

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: 0.307

Alfa AF: 0.324 Hom.: 1117

Bravo AF: 0.284

TwinsUK AF: 0.321 AC: 1189

ALSPAC AF: 0.321 AC: 1239

ExAC AF: 0.184 AC: 7078

Asia WGS AF: 0.230 AC: 794 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:10

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	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Spondylocostal dysostosis 1, autosomal recessive Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:2

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

Leukodystrophy and acquired microcephaly with or without dystonia; Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.55
DEOGEN2	Uncertain	0.62	.;D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	0.0015	P;P
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Benign	0.28
Sift	Benign	0.045	D;T
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.0080	.;B
Vest4		0.30
MPC		1.9
ClinPred		0.070	T
GERP RS		2.9
Varity_R		0.15

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: rs8107127; hg19: chr19-39993560;