19-39504071-T-C

Position:

chr19-39504071-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203486.3(DLL3):c.653T>C(p.Leu218Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,612,248 control chromosomes in the GnomAD database, including 241,474 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.59 ( 27535 hom., cov: 32)

Exomes 𝑓: 0.54 ( 213939 hom. )

Consequence

DLL3
NM_203486.3 missense, splice_region

Scores

Splicing: ADA: 0.00005985

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.45

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.636819E-6).

BP6

Variant 19-39504071-T-C is Benign according to our data. Variant chr19-39504071-T-C is described in ClinVar as [Benign]. Clinvar id is 41379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-39504071-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3 linkuse as main transcript	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	5/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4 linkuse as main transcript	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	5/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10 linkuse as main transcript	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	5/9	2	NM_203486.3	ENSP00000348810	P1	Q9NYJ7-2
DLL3	ENST00000205143.4 linkuse as main transcript	c.653T>C	p.Leu218Pro	missense_variant, splice_region_variant	5/8	1		ENSP00000205143		Q9NYJ7-1
DLL3	ENST00000600437.1 linkuse as main transcript	n.733T>C		splice_region_variant, non_coding_transcript_exon_variant	5/6	1
DLL3	ENST00000596614.5 linkuse as main transcript	c.410-2968T>C		intron_variant		2		ENSP00000471688

Frequencies

GnomAD3 genomes

AF:

0.594

AC:

90304

AN:

151990

Hom.:

27494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.722

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.556

Gnomad EAS

AF:

0.571

Gnomad SAS

AF:

0.582

Gnomad FIN

AF:

0.655

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.602

GnomAD3 exomes

AF:

0.563

AC:

140647

AN:

249764

Hom.:

40018

AF XY:

0.562

AC XY:

75896

AN XY:

135162

show subpopulations

Gnomad AFR exome

AF:

0.727

Gnomad AMR exome

AF:

0.532

Gnomad ASJ exome

AF:

0.563

Gnomad EAS exome

AF:

0.574

Gnomad SAS exome

AF:

0.562

Gnomad FIN exome

AF:

0.651

Gnomad NFE exome

AF:

0.531

Gnomad OTH exome

AF:

0.570

GnomAD4 exome

AF:

0.539

AC:

787206

AN:

1460140

Hom.:

213939

Cov.:

AF XY:

0.541

AC XY:

393009

AN XY:

726490

show subpopulations

Gnomad4 AFR exome

AF:

0.735

Gnomad4 AMR exome

AF:

0.531

Gnomad4 ASJ exome

AF:

0.558

Gnomad4 EAS exome

AF:

0.545

Gnomad4 SAS exome

AF:

0.563

Gnomad4 FIN exome

AF:

0.646

Gnomad4 NFE exome

AF:

0.524

Gnomad4 OTH exome

AF:

0.562

GnomAD4 genome

AF:

0.594

AC:

90397

AN:

152108

Hom.:

27535

Cov.:

AF XY:

0.599

AC XY:

44566

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.722

Gnomad4 AMR

AF:

0.524

Gnomad4 ASJ

AF:

0.556

Gnomad4 EAS

AF:

0.571

Gnomad4 SAS

AF:

0.582

Gnomad4 FIN

AF:

0.655

Gnomad4 NFE

AF:

0.529

Gnomad4 OTH

AF:

0.604

Alfa

AF:

0.544

Hom.:

32655

Bravo

AF:

0.588

TwinsUK

AF:

0.508

AC:

1883

ALSPAC

AF:

0.510

AC:

1965

ESP6500AA

AF:

0.720

AC:

3172

ESP6500EA

AF:

0.524

AC:

4503

ExAC

AF:

0.568

AC:

68908

Asia WGS

AF:

0.620

AC:

2156

AN:

3478

EpiCase

AF:

0.530

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Spondylocostal dysostosis 1, autosomal recessive

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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 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	-	- -

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

0.037

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

4.3

DANN

Benign

0.050

DEOGEN2

Benign

0.20

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-3.1

N;N

MutationTaster

Benign

0.50

P;P

PrimateAI

Benign

0.47

PROVEAN

Benign

3.4

N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T

Sift4G

Benign

0.45

T;T

Polyphen

0.0

.;B

Vest4

0.054

MPC

0.92

ClinPred

0.0060

GERP RS

0.83

Varity_R

0.039

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000060

dbscSNV1_RF

Benign

0.0080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over