rs104894676

chr19-39507456-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_203486.3(DLL3):c.1511G>A(p.Gly504Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,440,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.0740

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-39507456-G-A is Pathogenic according to our data. Variant chr19-39507456-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL3	NM_203486.3	c.1511G>A	p.Gly504Asp	missense_variant	7/9	ENST00000356433.10
DLL3	NM_016941.4	c.1511G>A	p.Gly504Asp	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL3	ENST00000356433.10	c.1511G>A	p.Gly504Asp	missense_variant	7/9	2	NM_203486.3	P1
DLL3	ENST00000205143.4	c.1511G>A	p.Gly504Asp	missense_variant	7/8	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 4 AN: 200636 Hom.: 0 AF XY: 0.00000903 AC XY: 1 AN XY: 110756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000467

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000701 AC: 101 AN: 1440926 Hom.: 0 Cov.: 31 AF XY: 0.0000713 AC XY: 51 AN XY: 714844

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000906

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000263 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2023	For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 6835). This missense change has been observed in individual(s) with clinical features of spondylocostal dysostosis (PMID: 15200511; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 504 of the DLL3 protein (p.Gly504Asp). -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

Spondylocostal dysostosis 1, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	20
Dann	Uncertain	0.98
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.00060	A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.63
Sift	Benign	0.15	T;T
Sift4G	Benign	0.070	T;T
Polyphen		0.74	.;P
Vest4		0.35
MVP		0.92
MPC		1.1
ClinPred		0.098	T
GERP RS		0.34
Varity_R		0.21

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: rs104894676; hg19: chr19-39998096;