rs1805389

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206937.2(LIG4):c.8C>T(p.Ala3Val) variant causes a missense change. The variant allele was found at a frequency of 0.0521 in 1,608,224 control chromosomes in the GnomAD database, including 2,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 207 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2254 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 4.99

Publications

41 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=0.0013820529).

BP6

Variant 13-108211261-G-A is Benign according to our data. Variant chr13-108211261-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2 link	c.8C>T	p.Ala3Val	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.8C>T	p.Ala3Val	missense_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1		P49917

Frequencies

GnomAD3 genomes

AF:

0.0452

AC:

6878

AN:

152098

Hom.:

207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00997

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.0497

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0488

Gnomad FIN

AF:

0.0573

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0583

Gnomad OTH

AF:

0.0355

GnomAD2 exomes

AF:

0.0567

AC:

13972

AN:

246410

AF XY:

0.0570

show subpopulations

Gnomad AFR exome

AF:

0.00971

Gnomad AMR exome

AF:

0.0559

Gnomad ASJ exome

AF:

0.0183

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.0588

Gnomad NFE exome

AF:

0.0574

Gnomad OTH exome

AF:

0.0444

GnomAD4 exome

AF:

0.0529

AC:

76987

AN:

1456008

Hom.:

2254

Cov.:

AF XY:

0.0531

AC XY:

38486

AN XY:

724460

show subpopulations

African (AFR)

AF:

0.00765

AC:

256

AN:

33458

American (AMR)

AF:

0.0579

AC:

2589

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

557

AN:

26122

East Asian (EAS)

AF:

0.0929

AC:

3685

AN:

39652

South Asian (SAS)

AF:

0.0509

AC:

4387

AN:

86150

European-Finnish (FIN)

AF:

0.0566

AC:

2935

AN:

51836

Middle Eastern (MID)

AF:

0.0502

AC:

283

AN:

5642

European-Non Finnish (NFE)

AF:

0.0535

AC:

59235

AN:

1108220

Other (OTH)

AF:

0.0508

AC:

3060

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

3470

6940

10409

13879

17349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2118

4236

6354

8472

10590

<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:

0.0452

AC:

6877

AN:

152216

Hom.:

207

Cov.:

AF XY:

0.0450

AC XY:

3352

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00994

AC:

413

AN:

41552

American (AMR)

AF:

0.0497

AC:

760

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

AN:

3470

East Asian (EAS)

AF:

0.114

AC:

593

AN:

5190

South Asian (SAS)

AF:

0.0494

AC:

238

AN:

4816

European-Finnish (FIN)

AF:

0.0573

AC:

607

AN:

10596

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0583

AC:

3963

AN:

67998

Other (OTH)

AF:

0.0342

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

343

685

1028

1370

1713

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0513

Hom.:

627

Bravo

AF:

0.0436

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0550

AC:

212

ESP6500AA

AF:

0.0121

AC:

ESP6500EA

AF:

0.0510

AC:

429

ExAC

AF:

0.0568

AC:

6872

Asia WGS

AF:

0.0680

AC:

238

AN:

3478

EpiCase

AF:

0.0557

EpiControl

AF:

0.0565

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 28, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

DNA ligase IV deficiency

Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Multiple myeloma, resistance to

Benign:1

Dec 01, 2002

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Severe combined immunodeficiency due to DCLRE1C deficiency

Benign:1

Mar 06, 2018

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

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

T;T;T;T

Eigen

Benign

0.0049

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.65

.;.;.;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L;L

PhyloP100

5.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.54

N;.;N;N

REVEL

Benign

0.090

Sift

Uncertain

0.013

D;.;D;D

Sift4G

Uncertain

0.027

D;D;D;D

Polyphen

0.38

B;B;B;B

Vest4

0.033

MPC

0.052

ClinPred

0.017

GERP RS

5.8

Varity_R

0.10

gMVP

0.35

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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