rs1805386

chr13-108209565-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_206937.2(LIG4):c.1704T>C(p.Asp568=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,942 control chromosomes in the GnomAD database, including 21,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1658 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19447 hom.)
• Consequence: LIG4 NM_206937.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.187

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-108209565-A-G is Benign according to our data. Variant chr13-108209565-A-G is described in ClinVar as [Benign]. Clinvar id is 129482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209565-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.187 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG4	NM_206937.2	c.1704T>C	p.Asp568=	synonymous_variant	3/3	ENST00000442234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG4	ENST00000442234.6	c.1704T>C	p.Asp568=	synonymous_variant	3/3	1	NM_206937.2	P1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20526 AN: 152044 Hom.: 1657 Cov.: 32

Gnomad AFR AF: 0.0738

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0594

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.134 AC: 33574 AN: 251374 Hom.: 2754 AF XY: 0.135 AC XY: 18380 AN XY: 135862

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0661

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.157 AC: 229760 AN: 1461780 Hom.: 19447 Cov.: 35 AF XY: 0.156 AC XY: 113188 AN XY: 727176

Gnomad4 AFR exome AF: 0.0716

Gnomad4 AMR exome AF: 0.0808

Gnomad4 ASJ exome AF: 0.196

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0686

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.135 AC: 20529 AN: 152162 Hom.: 1658 Cov.: 32 AF XY: 0.134 AC XY: 9966 AN XY: 74394

Gnomad4 AFR AF: 0.0737

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0605

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.176

Gnomad4 OTH AF: 0.155

Alfa AF: 0.163 Hom.: 1797

Bravo AF: 0.125

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.181

EpiControl AF: 0.176

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DNA ligase IV deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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 -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Severe combined immunodeficiency due to DCLRE1C deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.40
Dann	Benign	0.42

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

Other links and lift over

dbSNP: rs1805386; hg19: chr13-108861913; COSMIC: COSV105276683;