rs2232641

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_206937.2(LIG4):c.1972A>G(p.Ile658Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,614,092 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I658T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 32 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.480

Publications

21 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

LIG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046307743).

BP6

Variant 13-108209297-T-C is Benign according to our data. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209297-T-C is described in CliVar as Benign. Clinvar id is 695189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000913 (139/152316) while in subpopulation EAS AF = 0.0226 (117/5178). AF 95% confidence interval is 0.0193. There are 1 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2 link	c.1972A>G	p.Ile658Val	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
LIG4	ENST00000442234.6 link	c.1972A>G	p.Ile658Val	missense_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1		P49917

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0225

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00153

AC:

384

AN:

251284

AF XY:

0.00146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00110

AC:

1615

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

801

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33466

American (AMR)

AF:

0.000157

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0328

AC:

1301

AN:

39700

South Asian (SAS)

AF:

0.00191

AC:

165

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000540

AC:

AN:

1111942

Other (OTH)

AF:

0.00129

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

120

241

361

482

602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000913

AC:

139

AN:

152316

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.000131

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0226

AC:

117

AN:

5178

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000736

Hom.:

Bravo

AF:

0.000835

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00167

AC:

203

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DNA ligase IV deficiency

Benign:2

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Severe combined immunodeficiency due to DCLRE1C deficiency

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.58

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.10

T;T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.74

.;.;.;T;T

MetaRNN

Benign

0.0046

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.065

N;N;N;N;.

PhyloP100

-0.48

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.22

N;.;N;N;.

REVEL

Benign

0.19

Sift

Benign

1.0

T;.;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;B;B;.

Vest4

0.020

MVP

0.18

MPC

0.044

ClinPred

0.0099

GERP RS

-7.7

Varity_R

0.038

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over