rs8106337

Variant names:

• chr19-39502951-C-G
• rs8106337
• NM_203486.3:c.546C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-39502951-C-G
• chr19-39502951-C-T
• chr19-39502951-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203486.3(DLL3):​c.546C>G​(p.Ala182Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,451,786 control chromosomes in the GnomAD database, including 75,995 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. A182A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6461 hom., cov: 33)
  • Exomes 𝑓: 0.32 (69534 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0910
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 1, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-39502951-C-G is Benign according to our data. Variant chr19-39502951-C-G is described in ClinVar as Benign. ClinVar VariationId is 260780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.091 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	NM_203486.3	MANE Select	c.546C>G	p.Ala182Ala	synonymous	Exon 4 of 9	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.546C>G	p.Ala182Ala	synonymous	Exon 4 of 8	NP_058637.1	Q9NYJ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.546C>G	p.Ala182Ala	synonymous	Exon 4 of 9	ENSP00000348810.4	Q9NYJ7-2
	DLL3	ENST00000205143.4	TSL:1	c.546C>G	p.Ala182Ala	synonymous	Exon 4 of 8	ENSP00000205143.3	Q9NYJ7-1
	DLL3	ENST00000600437.1	TSL:1	n.626C>G		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42702 AN: 151790 Hom.: 6462 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.297 AC: 20055 AN: 67630 AF XY: 0.301

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.279

Gnomad EAS exome AF: 0.0793

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.323 AC: 419378 AN: 1299888 Hom.: 69534 Cov.: 37 AF XY: 0.324 AC XY: 207298 AN XY: 640080

African (AFR) AF: 0.163 AC: 4266 AN: 26106

American (AMR) AF: 0.285 AC: 6497 AN: 22794

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 6381 AN: 22312

East Asian (EAS) AF: 0.111 AC: 3149 AN: 28366

South Asian (SAS) AF: 0.326 AC: 22653 AN: 69508

European-Finnish (FIN) AF: 0.392 AC: 12700 AN: 32422

Middle Eastern (MID) AF: 0.371 AC: 1413 AN: 3806

European-Non Finnish (NFE) AF: 0.332 AC: 345569 AN: 1040894

Other (OTH) AF: 0.312 AC: 16750 AN: 53680

GnomAD4 genome AF: 0.281 AC: 42699 AN: 151898 Hom.: 6461 Cov.: 33 AF XY: 0.285 AC XY: 21182 AN XY: 74238

African (AFR) AF: 0.172 AC: 7120 AN: 41498

American (AMR) AF: 0.289 AC: 4408 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3470

East Asian (EAS) AF: 0.125 AC: 644 AN: 5160

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4824

European-Finnish (FIN) AF: 0.382 AC: 4013 AN: 10504

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.336 AC: 22817 AN: 67858

Other (OTH) AF: 0.295 AC: 623 AN: 2112

Alfa AF: 0.192 Hom.: 455

Bravo AF: 0.267

Asia WGS AF: 0.226 AC: 781 AN: 3456

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	3	Spondylocostal dysostosis 1, autosomal recessive (3)
-	-	2	not provided (2)
-	-	1	Syndactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.1
DANN	Benign	0.60
PhyloP100		-0.091
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8106337; hg19: chr19-39993591; COSMIC: COSV52696025; COSMIC: COSV52696025;