rs538355612

Variant names:

• chr13-108208367-C-G
• rs538355612
• NM_206937.2:c.*166G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_206937.2(LIG4):​c.*166G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 583,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: LIG4 NM_206937.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.449
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Dubowitz syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206937.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	NM_206937.2	MANE Select	c.*166G>C		3_prime_UTR	Exon 3 of 3	NP_996820.1	P49917
	LIG4	NM_001352604.2		c.*166G>C		3_prime_UTR	Exon 3 of 3	NP_001339533.1
	LIG4	NM_001098268.2		c.*166G>C		3_prime_UTR	Exon 2 of 2	NP_001091738.1	P49917

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.*166G>C		3_prime_UTR	Exon 3 of 3	ENSP00000402030.1	P49917
	LIG4	ENST00000405925.2	TSL:1	c.*166G>C		3_prime_UTR	Exon 2 of 2	ENSP00000385955.1	P49917
	LIG4	ENST00000611712.4	TSL:4	c.*166G>C		3_prime_UTR	Exon 3 of 3	ENSP00000484288.1	P49917

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000677

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000397 AC: 171 AN: 431106 Hom.: 1 Cov.: 5 AF XY: 0.000401 AC XY: 92 AN XY: 229342

African (AFR) AF: 0.000250 AC: 3 AN: 12000

American (AMR) AF: 0.000959 AC: 15 AN: 15636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12994

East Asian (EAS) AF: 0.00 AC: 0 AN: 29088

South Asian (SAS) AF: 0.00 AC: 0 AN: 42300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1946

European-Non Finnish (NFE) AF: 0.000522 AC: 139 AN: 266244

Other (OTH) AF: 0.000567 AC: 14 AN: 24692

GnomAD4 genome AF: 0.000539 AC: 82 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000539 AC XY: 40 AN XY: 74278

African (AFR) AF: 0.000217 AC: 9 AN: 41422

American (AMR) AF: 0.00170 AC: 26 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000677 AC: 46 AN: 67974

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000559

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	DNA ligase IV deficiency (1)
-	1	-	Severe combined immunodeficiency due to DCLRE1C deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.2
DANN	Benign	0.45
PhyloP100		-0.45

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

Other links and lift over

dbSNP: rs538355612; hg19: chr13-108860715;