rs8107127

Variant names:

• chr19-39502920-T-G
• rs8107127
• NM_203486.3:c.515T>G
• DLL3 p.Phe172Cys

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203486.3(DLL3):​c.515T>G​(p.Phe172Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,441,728 control chromosomes in the GnomAD database, including 75,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (6867 hom., cov: 32)
  • Exomes 𝑓: 0.32 (69010 hom.)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.06
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031743944).
• BP6: Variant 19-39502920-T-G is Benign according to our data. Variant chr19-39502920-T-G is described in ClinVar as Benign. ClinVar VariationId is 41378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.515T>G	p.Phe172Cys	missense	Exon 4 of 9	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.515T>G	p.Phe172Cys	missense	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.515T>G	p.Phe172Cys	missense	Exon 4 of 9	ENSP00000348810.4	Q9NYJ7-2
	DLL3	ENST00000205143.4	TSL:1	c.515T>G	p.Phe172Cys	missense	Exon 4 of 8	ENSP00000205143.3	Q9NYJ7-1
	DLL3	ENST00000600437.1	TSL:1	n.595T>G		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44968 AN: 151694 Hom.: 6865 Cov.: 32

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.295

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: 0.312

GnomAD2 exomes AF: 0.286 AC: 17935 AN: 62816 AF XY: 0.290

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.0758

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.323 AC: 416975 AN: 1289922 Hom.: 69010 Cov.: 36 AF XY: 0.324 AC XY: 205878 AN XY: 634828

African (AFR) AF: 0.215 AC: 5566 AN: 25884

American (AMR) AF: 0.279 AC: 5951 AN: 21318

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 6149 AN: 21828

East Asian (EAS) AF: 0.111 AC: 3123 AN: 28100

South Asian (SAS) AF: 0.323 AC: 21969 AN: 68058

European-Finnish (FIN) AF: 0.390 AC: 12537 AN: 32118

Middle Eastern (MID) AF: 0.373 AC: 1402 AN: 3762

European-Non Finnish (NFE) AF: 0.332 AC: 343527 AN: 1035646

Other (OTH) AF: 0.315 AC: 16751 AN: 53208

GnomAD4 genome AF: 0.296 AC: 44974 AN: 151806 Hom.: 6867 Cov.: 32 AF XY: 0.300 AC XY: 22261 AN XY: 74198

African (AFR) AF: 0.224 AC: 9280 AN: 41462

American (AMR) AF: 0.295 AC: 4502 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1018 AN: 3470

East Asian (EAS) AF: 0.125 AC: 639 AN: 5132

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4822

European-Finnish (FIN) AF: 0.382 AC: 4013 AN: 10514

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

European-Non Finnish (NFE) AF: 0.336 AC: 22815 AN: 67824

Other (OTH) AF: 0.307 AC: 650 AN: 2114

Alfa AF: 0.309 Hom.: 2306

Bravo AF: 0.284

Asia WGS AF: 0.230 AC: 794 AN: 3460

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	Leukodystrophy and acquired microcephaly with or without dystonia; (1)
-	-	1	Syndactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.55
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.28
Sift	Benign	0.045	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.15
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs8107127;

hg19: chr19-39993560;

COSMIC: COSV107222231;