NM_203486.3:c.153C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_203486.3(DLL3):​c.153C>T​(p.Ser51Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,541,584 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

DLL3
NM_203486.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.277

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: Labcorp Genetics (formerly Invitae), G2P
  • autosomal recessive spondylocostal dysostosis
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.63).
BP6
Variant 19-39499275-C-T is Benign according to our data. Variant chr19-39499275-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260775.
BP7
Synonymous conserved (PhyloP=-0.277 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000597 (91/152346) while in subpopulation AMR AF = 0.000849 (13/15306). AF 95% confidence interval is 0.000502. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DLL3NM_203486.3 linkc.153C>T p.Ser51Ser synonymous_variant Exon 2 of 9 ENST00000356433.10 NP_982353.1 Q9NYJ7-2
DLL3NM_016941.4 linkc.153C>T p.Ser51Ser synonymous_variant Exon 2 of 8 NP_058637.1 Q9NYJ7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DLL3ENST00000356433.10 linkc.153C>T p.Ser51Ser synonymous_variant Exon 2 of 9 2 NM_203486.3 ENSP00000348810.4 Q9NYJ7-2

Frequencies

GnomAD3 genomes
AF:
0.000598
AC:
91
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000675
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000850
Gnomad ASJ
AF:
0.00317
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.000496
AC:
68
AN:
137080
AF XY:
0.000575
show subpopulations
Gnomad AFR exome
AF:
0.000300
Gnomad AMR exome
AF:
0.000202
Gnomad ASJ exome
AF:
0.00367
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000509
Gnomad OTH exome
AF:
0.000972
GnomAD4 exome
AF:
0.000327
AC:
454
AN:
1389238
Hom.:
0
Cov.:
33
AF XY:
0.000350
AC XY:
240
AN XY:
685926
show subpopulations
African (AFR)
AF:
0.000190
AC:
6
AN:
31598
American (AMR)
AF:
0.000306
AC:
11
AN:
35910
Ashkenazi Jewish (ASJ)
AF:
0.00401
AC:
101
AN:
25162
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35882
South Asian (SAS)
AF:
0.0000377
AC:
3
AN:
79628
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
38924
Middle Eastern (MID)
AF:
0.00250
AC:
11
AN:
4396
European-Non Finnish (NFE)
AF:
0.000256
AC:
276
AN:
1079882
Other (OTH)
AF:
0.000795
AC:
46
AN:
57856
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
36
72
108
144
180
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.000597
AC:
91
AN:
152346
Hom.:
0
Cov.:
32
AF XY:
0.000604
AC XY:
45
AN XY:
74496
show subpopulations
African (AFR)
AF:
0.000673
AC:
28
AN:
41578
American (AMR)
AF:
0.000849
AC:
13
AN:
15306
Ashkenazi Jewish (ASJ)
AF:
0.00317
AC:
11
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4830
European-Finnish (FIN)
AF:
0.0000941
AC:
1
AN:
10626
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000426
AC:
29
AN:
68034
Other (OTH)
AF:
0.00236
AC:
5
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000755
Hom.:
0
Bravo
AF:
0.000642

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Spondylocostal dysostosis 1, autosomal recessive Uncertain:1Benign:1
Oct 11, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Syndactyly Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Sep 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.63
CADD
Benign
5.8
DANN
Benign
0.91
PhyloP100
-0.28
PromoterAI
0.0051
Neutral
Mutation Taster
=100/0
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

Publications

Other links and lift over

dbSNP: rs373980582; hg19: chr19-39989915; API