rs1805388

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_206937.2(LIG4):c.26C>T(p.Thr9Ile) variant causes a missense change. The variant allele was found at a frequency of 0.165 in 1,610,136 control chromosomes in the GnomAD database, including 23,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2252 hom., cov: 32)

Exomes 𝑓: 0.16 ( 21217 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 4.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015589893).

BP6

Variant 13-108211243-G-A is Benign according to our data. Variant chr13-108211243-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 7677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108211243-G-A is described in Lovd as [Benign]. Variant chr13-108211243-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG4	NM_206937.2 linkuse as main transcript	c.26C>T	p.Thr9Ile	missense_variant	3/3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6 linkuse as main transcript	c.26C>T	p.Thr9Ile	missense_variant	3/3	1	NM_206937.2	ENSP00000402030	P1

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24709

AN:

151982

Hom.:

2250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.284

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.0977

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.0892

Gnomad FIN

AF:

0.295

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.172

Gnomad OTH

AF:

0.131

GnomAD3 exomes

AF:

0.177

AC:

43666

AN:

247176

Hom.:

4384

AF XY:

0.170

AC XY:

22884

AN XY:

134540

show subpopulations

Gnomad AFR exome

AF:

0.107

Gnomad AMR exome

AF:

0.235

Gnomad ASJ exome

AF:

0.0859

Gnomad EAS exome

AF:

0.227

Gnomad SAS exome

AF:

0.0877

Gnomad FIN exome

AF:

0.284

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.159

GnomAD4 exome

AF:

0.165

AC:

240295

AN:

1458036

Hom.:

21217

Cov.:

AF XY:

0.162

AC XY:

117597

AN XY:

725348

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.231

Gnomad4 ASJ exome

AF:

0.0894

Gnomad4 EAS exome

AF:

0.166

Gnomad4 SAS exome

AF:

0.0865

Gnomad4 FIN exome

AF:

0.280

Gnomad4 NFE exome

AF:

0.168

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.163

AC:

24721

AN:

152100

Hom.:

2252

Cov.:

AF XY:

0.168

AC XY:

12458

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.205

Gnomad4 ASJ

AF:

0.0977

Gnomad4 EAS

AF:

0.219

Gnomad4 SAS

AF:

0.0895

Gnomad4 FIN

AF:

0.295

Gnomad4 NFE

AF:

0.172

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.160

Hom.:

4295

Bravo

AF:

0.154

TwinsUK

AF:

0.169

AC:

628

ALSPAC

AF:

0.174

AC:

670

ESP6500AA

AF:

0.103

AC:

450

ESP6500EA

AF:

0.155

AC:

1310

ExAC

AF:

0.169

AC:

20477

Asia WGS

AF:

0.152

AC:

531

AN:

3478

EpiCase

AF:

0.152

EpiControl

AF:

0.156

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, Clinvar assertions are benign and protective (not pathogenic) -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

DNA ligase IV deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:2Other:1

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Multiple myeloma, resistance to

Benign:1

protective, no assertion criteria provided

literature only

OMIM

May 18, 2015

- -

Severe combined immunodeficiency due to DCLRE1C deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;D;D

Eigen

Benign

-0.093

Eigen_PC

Benign

0.045

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.74

.;.;.;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.0

M;M;M;M

MutationTaster

Benign

0.19

P;P;P

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.7

D;.;D;D

REVEL

Benign

0.073

Sift

Uncertain

0.0030

D;.;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.52

P;P;P;P

Vest4

0.089

MPC

0.059

ClinPred

0.030

GERP RS

4.1

Varity_R

0.16

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over