19-39499275-C-T

Variant names:

• chr19-39499275-C-T
• rs373980582
• NM_203486.3:c.153C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6 BP7 BS1

The NM_203486.3(DLL3):​c.153C>T​(p.Ser51Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,541,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.277

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-39499275-C-T is Benign according to our data. Variant chr19-39499275-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260775.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-0.277 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000597 (91/152346) while in subpopulation AMR AF= 0.000849 (13/15306). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3	c.153C>T	p.Ser51Ser	synonymous_variant	Exon 2 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.153C>T	p.Ser51Ser	synonymous_variant	Exon 2 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.153C>T	p.Ser51Ser	synonymous_variant	Exon 2 of 9	2	NM_203486.3	ENSP00000348810.4

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000496 AC: 68 AN: 137080 Hom.: 0 AF XY: 0.000575 AC XY: 43 AN XY: 74836

Gnomad AFR exome AF: 0.000300

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000509

Gnomad OTH exome AF: 0.000972

GnomAD4 exome AF: 0.000327 AC: 454 AN: 1389238 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 240 AN XY: 685926

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000306

Gnomad4 ASJ exome AF: 0.00401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000377

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74496

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000755 Hom.: 0

Bravo AF: 0.000642

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive Uncertain:1 Benign:1

Oct 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Syndactyly Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.8
DANN	Benign	0.91

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: rs373980582; hg19: chr19-39989915;