rs115456333

Positions:

• chr19-39507097-G-A
• chr19-39507097-G-C
• chr19-39507097-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_203486.3(DLL3):​c.1152G>A​(p.Ala384=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,543,398 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A384A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (43 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.565

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-39507097-G-A is Benign according to our data. Variant chr19-39507097-G-A is described in ClinVar as [Benign]. Clinvar id is 260773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.565 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0142 (2157/152152) while in subpopulation AFR AF= 0.0487 (2022/41546). AF 95% confidence interval is 0.0469. There are 41 homozygotes in gnomad4. There are 1021 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLL3	NM_203486.3	c.1152G>A	p.Ala384=	synonymous_variant	7/9	ENST00000356433.10
DLL3	NM_016941.4	c.1152G>A	p.Ala384=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLL3	ENST00000356433.10	c.1152G>A	p.Ala384=	synonymous_variant	7/9	2	NM_203486.3	P1
DLL3	ENST00000205143.4	c.1152G>A	p.Ala384=	synonymous_variant	7/8	1
DLL3	ENST00000596614.5	c.468G>A	p.Ala156=	synonymous_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2153 AN: 152038 Hom.: 41 Cov.: 31

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

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: 0.000309

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00303 AC: 434 AN: 143154 Hom.: 11 AF XY: 0.00254 AC XY: 200 AN XY: 78852

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.000122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000857

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000249

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.00143 AC: 1993 AN: 1391246 Hom.: 43 Cov.: 31 AF XY: 0.00123 AC XY: 848 AN XY: 687682

Gnomad4 AFR exome AF: 0.0490

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000875

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.00309

GnomAD4 genome AF: 0.0142 AC: 2157 AN: 152152 Hom.: 41 Cov.: 31 AF XY: 0.0137 AC XY: 1021 AN XY: 74398

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.00589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00194 Hom.: 1

Bravo AF: 0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 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:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.0
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115456333; hg19: chr19-39997737;