rs551263548

Variant names:

• chr13-108208529-AG-A
• rs551263548
• NM_206937.2:c.*3delC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_206937.2(LIG4):​c.*3delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,591,694 control chromosomes in the GnomAD database, including 50 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (44 hom.)
• Consequence: LIG4 NM_206937.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.275

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 -16 ACMG points.

• BP6: Variant 13-108208529-AG-A is Benign according to our data. Variant chr13-108208529-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 465278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00582 (886/152336) while in subpopulation NFE AF= 0.00783 (533/68032). AF 95% confidence interval is 0.00728. There are 6 homozygotes in gnomad4. There are 455 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2	c.*3delC		3_prime_UTR_variant	Exon 3 of 3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234	c.*3delC		3_prime_UTR_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152218 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00565 AC: 1394 AN: 246836 Hom.: 8 AF XY: 0.00572 AC XY: 765 AN XY: 133676

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00191

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000396

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.00521 AC: 7502 AN: 1439358 Hom.: 44 Cov.: 28 AF XY: 0.00529 AC XY: 3796 AN XY: 717292

Gnomad4 AFR exome AF: 0.000667

Gnomad4 AMR exome AF: 0.00292

Gnomad4 ASJ exome AF: 0.00243

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000316

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.00555

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152336 Hom.: 6 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74500

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.00783

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00758 Hom.: 1

Bravo AF: 0.00476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26774591) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LIG4: BS2 -

DNA ligase IV deficiency Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LIG4-related disorder Benign:1

Sep 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs551263548; hg19: chr13-108860877;