13-108210578-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP6

The NM_206937.2(LIG4):​c.691C>T​(p.Pro231Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,044 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 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

4
11
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 9.51

Publications

3 publications found
Variant links:
Genes affected
LIG4 (HGNC:6601): (DNA ligase 4) The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
LIG4 Gene-Disease associations (from GenCC):
  • DNA ligase IV deficiency
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
  • Dubowitz syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Omenn syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.32838106).
BP6
Variant 13-108210578-G-A is Benign according to our data. Variant chr13-108210578-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 834697.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LIG4NM_206937.2 linkc.691C>T p.Pro231Ser missense_variant Exon 3 of 3 ENST00000442234.6 NP_996820.1 P49917A0A024RE06

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LIG4ENST00000442234.6 linkc.691C>T p.Pro231Ser missense_variant Exon 3 of 3 1 NM_206937.2 ENSP00000402030.1 P49917

Frequencies

GnomAD3 genomes
AF:
0.000427
AC:
65
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00147
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000124
AC:
31
AN:
250152
AF XY:
0.0000665
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1460870
Hom.:
0
Cov.:
33
AF XY:
0.0000220
AC XY:
16
AN XY:
726750
show subpopulations
African (AFR)
AF:
0.00128
AC:
43
AN:
33476
American (AMR)
AF:
0.000268
AC:
12
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86246
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5738
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111904
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
3
7
10
14
17
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000427
AC:
65
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.000377
AC XY:
28
AN XY:
74342
show subpopulations
African (AFR)
AF:
0.00147
AC:
61
AN:
41426
American (AMR)
AF:
0.000262
AC:
4
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
4
8
11
15
19
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:
0.000309
Hom.:
0
Bravo
AF:
0.000465
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000148
AC:
18

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 06, 2022
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

DNA sequence analysis of the LIG4 gene demonstrated a sequence change, c.691C>T, in exon 2 that results in an amino acid change, p.Pro231Ser. This sequence change does not appear to have been previously described in individuals with LIG4-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.1485% in the African/African American subpopulation (dbSNP rs3093765). The p.Pro231Ser change affects a highly conserved amino acid residue located in a domain of the LIG4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro231Ser substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro231Ser change remains unknown at this time. -

Multiple myeloma;C1847827:DNA ligase IV deficiency Uncertain:1
Apr 05, 2022
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

DNA ligase IV deficiency Benign:1
Jan 01, 2025
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
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.62
D;D;D;D;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
.;.;.;D;D
M_CAP
Uncertain
0.089
D
MetaRNN
Benign
0.33
T;T;T;T;T
MetaSVM
Uncertain
-0.081
T
MutationAssessor
Pathogenic
3.0
M;M;M;M;.
PhyloP100
9.5
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.0
D;.;D;D;.
REVEL
Uncertain
0.55
Sift
Uncertain
0.0060
D;.;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.78
P;P;P;P;.
Vest4
0.68
MVP
0.81
MPC
0.092
ClinPred
0.16
T
GERP RS
5.7
Varity_R
0.60
gMVP
0.55
Mutation Taster
=55/45
polymorphism

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

Other links and lift over

dbSNP: rs3093765; hg19: chr13-108862926; COSMIC: COSV63596404; API