rs370390772

Variant names:

• chr19-39499197-G-A
• rs370390772
• NM_203486.3:c.75G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-39499197-G-A
• chr19-39499197-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_203486.3(DLL3):​c.75G>A​(p.Arg25Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,576,322 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R25R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DLL3 NM_203486.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0320
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-39499197-G-A is Benign according to our data. Variant chr19-39499197-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2072607.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.032 with no splicing effect.

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.75G>A	p.Arg25Arg	synonymous	Exon 2 of 9	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.75G>A	p.Arg25Arg	synonymous	Exon 2 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.75G>A	p.Arg25Arg	synonymous	Exon 2 of 9	ENSP00000348810.4	Q9NYJ7-2
	DLL3	ENST00000205143.4	TSL:1	c.75G>A	p.Arg25Arg	synonymous	Exon 2 of 8	ENSP00000205143.3	Q9NYJ7-1
	DLL3	ENST00000600437.1	TSL:1	n.155G>A		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000434 AC: 8 AN: 184124 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000169 AC: 24 AN: 1424014 Hom.: 0 Cov.: 33 AF XY: 0.0000184 AC XY: 13 AN XY: 706770

African (AFR) AF: 0.00 AC: 0 AN: 32552

American (AMR) AF: 0.00 AC: 0 AN: 39708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.000213 AC: 8 AN: 37642

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4696

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1098206

Other (OTH) AF: 0.0000338 AC: 2 AN: 59132

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152308 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		0.032
PromoterAI		-0.040	Neutral

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: rs370390772; hg19: chr19-39989837;