rs142957638

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_206937.2(LIG4):c.686A>G(p.His229Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,613,382 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H229H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 1 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.60

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0107935965).

BP6

Variant 13-108210583-T-C is Benign according to our data. Variant chr13-108210583-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211376.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00171 (260/152350) while in subpopulation AFR AF = 0.00618 (257/41582). AF 95% confidence interval is 0.00556. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2 link	c.686A>G	p.His229Arg	missense_variant	Exon 3 of 3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6 link	c.686A>G	p.His229Arg	missense_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00620

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000956

GnomAD2 exomes

AF:

0.000488

AC:

122

AN:

250222

AF XY:

0.000355

show subpopulations

Gnomad AFR exome

AF:

0.00648

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461032

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.00615

AC:

206

AN:

33476

American (AMR)

AF:

0.000157

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000126

AC:

AN:

39680

South Asian (SAS)

AF:

0.000162

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111932

Other (OTH)

AF:

0.000182

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00171

AC:

260

AN:

152350

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00618

AC:

257

AN:

41582

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000814

Hom.:

Bravo

AF:

0.00202

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 04, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Mar 05, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DNA ligase IV deficiency

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LIG4-related disorder

Benign:1

Mar 09, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

T;T;T;T;.

Eigen

Benign

0.047

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

.;.;.;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;L;L;.

PhyloP100

7.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.4

N;.;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.25

T;.;T;T;.

Sift4G

Benign

0.22

T;T;T;T;T

Polyphen

0.069

B;B;B;B;.

Vest4

0.76

MVP

0.48

MPC

0.059

ClinPred

0.061

GERP RS

5.7

Varity_R

0.47

gMVP

0.57

Mutation Taster

=20/80

disease causing

(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