13-108211061-G-C

Variant names:

• chr13-108211061-G-C
• rs193107403
• NM_206937.2:c.208C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_206937.2(LIG4):​c.208C>G​(p.Leu70Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L70P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIG4 NM_206937.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Dubowitz syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	NM_206937.2	MANE Select	c.208C>G	p.Leu70Val	missense	Exon 3 of 3	NP_996820.1
	LIG4	NM_001352604.2		c.244C>G	p.Leu82Val	missense	Exon 3 of 3	NP_001339533.1
	LIG4	NM_001098268.2		c.208C>G	p.Leu70Val	missense	Exon 2 of 2	NP_001091738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.208C>G	p.Leu70Val	missense	Exon 3 of 3	ENSP00000402030.1
	LIG4	ENST00000405925.2	TSL:1	c.208C>G	p.Leu70Val	missense	Exon 2 of 2	ENSP00000385955.1
	LIG4	ENST00000611712.4	TSL:4	c.208C>G	p.Leu70Val	missense	Exon 3 of 3	ENSP00000484288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244710 AF XY: 0.00000756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.89e-7 AC: 1 AN: 1450936 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 720550

African (AFR) AF: 0.00 AC: 0 AN: 32824

American (AMR) AF: 0.00 AC: 0 AN: 43178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25680

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106844

Other (OTH) AF: 0.00 AC: 0 AN: 59876

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	DNA ligase IV deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.75		Gain of catalytic residue at P73 (P = 0.0068)
MVP		0.49
MPC		0.34
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.89
gMVP		0.68
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs193107403; hg19: chr13-108863409;