rs199831437

Positions:

chr19-39507252-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_203486.3(DLL3):c.1307G>A(p.Arg436His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000626 in 1,508,872 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

DLL3
NM_203486.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.269

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009253353).

BP6

Variant 19-39507252-G-A is Benign according to our data. Variant chr19-39507252-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-39507252-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00293 (444/151500) while in subpopulation AFR AF= 0.0102 (423/41448). AF 95% confidence interval is 0.0094. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLL3	NM_203486.3 linkuse as main transcript	c.1307G>A	p.Arg436His	missense_variant	7/9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4 linkuse as main transcript	c.1307G>A	p.Arg436His	missense_variant	7/8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10 linkuse as main transcript	c.1307G>A	p.Arg436His	missense_variant	7/9	2	NM_203486.3	ENSP00000348810	P1	Q9NYJ7-2
DLL3	ENST00000205143.4 linkuse as main transcript	c.1307G>A	p.Arg436His	missense_variant	7/8	1		ENSP00000205143		Q9NYJ7-1
DLL3	ENST00000596614.5 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	4/4	2		ENSP00000471688

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

441

AN:

151392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000527

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.000528

AC:

AN:

106144

Hom.:

AF XY:

0.000439

AC XY:

AN XY:

59254

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.000687

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000503

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00122

GnomAD4 exome

AF:

0.000368

AC:

500

AN:

1357372

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

236

AN XY:

669746

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.000807

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000261

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.000761

GnomAD4 genome

AF:

0.00293

AC:

444

AN:

151500

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

200

AN XY:

74066

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.000526

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00328

ExAC

AF:

0.000254

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2017	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Spondylocostal dysostosis 1, autosomal recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;.;T

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.083

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.52

T;D;T

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

-0.035

N;.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.68

N;.;N

REVEL

Benign

0.23

Sift

Benign

0.18

T;.;T

Sift4G

Benign

0.092

T;T;T

Polyphen

0.99

.;.;D

Vest4

0.31

MVP

0.95

MPC

1.7

ClinPred

0.038

GERP RS

3.4

Varity_R

0.042

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

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