rs1805389

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.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. 13/20 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

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=0.0013820529).

BP6

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

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/exons	MANE	UniProt
LIG4	NM_206937.2 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	3/3	ENST00000442234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG4	ENST00000442234.6 linkuse as main transcript	c.8C>T	p.Ala3Val	missense_variant	3/3	1	NM_206937.2	P1

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

GnomAD3 exomes

AF:

0.0567

AC:

13972

AN:

246410

Hom.:

498

AF XY:

0.0570

AC XY:

7660

AN XY:

134362

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 SAS exome

AF:

0.0520

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

Gnomad4 AFR exome

AF:

0.00765

Gnomad4 AMR exome

AF:

0.0579

Gnomad4 ASJ exome

AF:

0.0213

Gnomad4 EAS exome

AF:

0.0929

Gnomad4 SAS exome

AF:

0.0509

Gnomad4 FIN exome

AF:

0.0566

Gnomad4 NFE exome

AF:

0.0535

Gnomad4 OTH exome

AF:

0.0508

GnomAD4 genome

AF:

0.0452

AC:

6877

AN:

152216

Hom.:

207

Cov.:

AF XY:

0.0450

AC XY:

3352

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00994

Gnomad4 AMR

AF:

0.0497

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.0494

Gnomad4 FIN

AF:

0.0573

Gnomad4 NFE

AF:

0.0583

Gnomad4 OTH

AF:

0.0342

Alfa

AF:

0.0526

Hom.:

378

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 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. -

DNA ligase IV deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Mar 06, 2018	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. -

not provided

Benign:2Other:1

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Multiple myeloma, resistance to

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

Severe combined immunodeficiency due to DCLRE1C deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

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

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

MutationTaster

Benign

0.95

P;P;P

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

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

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