NM_206937.2:c.2222G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_206937.2(LIG4):c.2222G>A(p.Arg741His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000291 in 1,613,954 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.92

Publications

4 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=0.0073931515).

BP6

Variant 13-108209047-C-T is Benign according to our data. Variant chr13-108209047-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 310979.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2 link	c.2222G>A	p.Arg741His	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.2222G>A	p.Arg741His	missense_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1		P49917

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000613

AC:

154

AN:

251176

AF XY:

0.000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0122

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000278

AC:

406

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

214

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

278

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000621

AC:

AN:

1112000

Other (OTH)

AF:

0.000778

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

122

153

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:

0.000421

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000575

Hom.:

Bravo

AF:

0.000366

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DNA ligase IV deficiency

Uncertain:1Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

Severe combined immunodeficiency due to DCLRE1C deficiency

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Jan 05, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jun 28, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;T;T;T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.028

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.61

.;.;.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.0074

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;L;L;L;.

PhyloP100

2.9

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

N;.;N;N;.

REVEL

Benign

0.059

Sift

Benign

0.17

T;.;T;T;.

Sift4G

Benign

0.13

T;T;T;T;T

Polyphen

0.026

B;B;B;B;.

Vest4

0.060

MVP

0.49

MPC

0.058

ClinPred

0.025

GERP RS

3.2

Varity_R

0.085

gMVP

0.63

Mutation Taster

=75/25

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