chr19-39498996-G-A

Variant names:

• chr19-39498996-G-A
• NM_203486.3:c.22G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_203486.3(DLL3):​c.22G>A​(p.Gly8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DLL3 NM_203486.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0910

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049122244).
• BP6: Variant 19-39498996-G-A is Benign according to our data. Variant chr19-39498996-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3502450.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLL3	NM_203486.3	c.22G>A	p.Gly8Arg	missense_variant	Exon 1 of 9	ENST00000356433.10	NP_982353.1
DLL3	NM_016941.4	c.22G>A	p.Gly8Arg	missense_variant	Exon 1 of 8		NP_058637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLL3	ENST00000356433.10	c.22G>A	p.Gly8Arg	missense_variant	Exon 1 of 9	2	NM_203486.3	ENSP00000348810.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Nov 09, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.1
DANN	Benign	0.91
DEOGEN2	Benign	0.21	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.24	T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.34	N;.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.77	N;.;N
REVEL	Benign	0.10
Sift	Benign	0.77	T;.;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.083
MutPred		0.31		Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);
MVP		0.76
MPC		0.69
ClinPred		0.038	T
GERP RS		1.2
Varity_R		0.068

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-39989636;