chr19-39507097-G-A

Variant names:

• chr19-39507097-G-A
• rs115456333
• NM_203486.3:c.1152G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_016941.4(DLL3):​c.1152G>A​(p.Ala384Ala) 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_016941.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.565
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016941.4. 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.1152G>A	p.Ala384Ala	synonymous	Exon 7 of 9	NP_982353.1
	DLL3	NM_016941.4		c.1152G>A	p.Ala384Ala	synonymous	Exon 7 of 8	NP_058637.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLL3	ENST00000356433.10	TSL:2 MANE Select	c.1152G>A	p.Ala384Ala	synonymous	Exon 7 of 9	ENSP00000348810.4
	DLL3	ENST00000205143.4	TSL:1	c.1152G>A	p.Ala384Ala	synonymous	Exon 7 of 8	ENSP00000205143.3
	DLL3	ENST00000913807.1		c.1140G>A	p.Ala380Ala	synonymous	Exon 7 of 9	ENSP00000583866.1

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

GnomAD2 exomes AF: 0.00303 AC: 434 AN: 143154 AF XY: 0.00254

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 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

African (AFR) AF: 0.0490 AC: 1563 AN: 31914

American (AMR) AF: 0.00305 AC: 115 AN: 37682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 36372

South Asian (SAS) AF: 0.0000875 AC: 7 AN: 79976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33904

Middle Eastern (MID) AF: 0.00274 AC: 12 AN: 4386

European-Non Finnish (NFE) AF: 0.000108 AC: 117 AN: 1083854

Other (OTH) AF: 0.00309 AC: 179 AN: 57992

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

African (AFR) AF: 0.0487 AC: 2022 AN: 41546

American (AMR) AF: 0.00589 AC: 90 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67968

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00301 Hom.: 1

Bravo AF: 0.0159

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.0
DANN	Benign	0.92
PhyloP100		-0.56
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs115456333; hg19: chr19-39997737;