Genetic Variant NM_203486.3:c.-12dupC (chr19-39498956-A-AC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_203486.3(DLL3):c.-12dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000472 in 1,609,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

DLL3
NM_203486.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.75

Publications

0 publications found

Variant links:

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

DLL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000452 (66/1461618) while in subpopulation EAS AF = 0.000932 (37/39696). AF 95% confidence interval is 0.000694. There are 0 homozygotes in GnomAdExome4. There are 26 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-12dupC		5_prime_UTR	Exon 1 of 9	NP_982353.1	Q9NYJ7-2
	DLL3	NM_016941.4		c.-12dupC		5_prime_UTR	Exon 1 of 8	NP_058637.1	Q9NYJ7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DLL3	ENST00000356433.10	TSL:2 MANE Select	c.-12dupC	5_prime_UTR	Exon 1 of 9	ENSP00000348810.4	Q9NYJ7-2
DLL3	ENST00000600437.1	TSL:1	n.69dupC	non_coding_transcript_exon	Exon 1 of 6
DLL3	ENST00000913807.1		c.-12dupC	5_prime_UTR	Exon 1 of 9	ENSP00000583866.1

Frequencies

GnomAD3 genomes

AF:

0.0000675

AC:

AN:

148054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000504

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000599

Gnomad SAS

AF:

0.00108

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000718

AC:

AN:

250802

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000816

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000932

AC:

AN:

39696

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111962

Other (OTH)

AF:

0.0000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000675

AC:

AN:

148054

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

AN XY:

72096

show subpopulations

African (AFR)

AF:

0.0000504

AC:

AN:

39674

American (AMR)

AF:

0.00

AC:

AN:

14932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.000599

AC:

AN:

5008

South Asian (SAS)

AF:

0.00108

AC:

AN:

4644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67030

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Spondylocostal dysostosis (1)

Syndactyly (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over