rs143767581

Variant names:

• chr13-108209047-C-A
• NM_206937.2:c.2222G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-108209047-C-A
• chr13-108209047-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_206937.2(LIG4):​c.2222G>T​(p.Arg741Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIG4 NM_206937.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.92

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3219929).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2	c.2222G>T	p.Arg741Leu	missense_variant	Exon 3 of 3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6	c.2222G>T	p.Arg741Leu	missense_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0051	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D;D;D;.
Eigen	Benign	-0.0026
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	.;.;.;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M;M;M;M;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.0	N;.;N;N;.
REVEL	Benign	0.27
Sift	Benign	0.14	T;.;T;T;.
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.27	B;B;B;B;.
Vest4		0.40
MutPred		0.55		Gain of catalytic residue at H745 (P = 2e-04);Gain of catalytic residue at H745 (P = 2e-04);Gain of catalytic residue at H745 (P = 2e-04);Gain of catalytic residue at H745 (P = 2e-04);.;
MVP		0.45
MPC		0.059
ClinPred		0.69	D
GERP RS		3.2
Varity_R		0.22
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-108861395;