rs552242241

Positions:

• chr13-108209662-C-G
• chr13-108209662-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000442234.6(LIG4):​c.1607G>C​(p.Ser536Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S536N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIG4 ENST00000442234.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06591433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG4	NM_206937.2	c.1607G>C	p.Ser536Thr	missense_variant	3/3	ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6	c.1607G>C	p.Ser536Thr	missense_variant	3/3	1	NM_206937.2	ENSP00000402030	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.32
DEOGEN2	Benign	0.062	T;T;T;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.66	.;.;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.78	N;.;N;N;.
REVEL	Benign	0.035
Sift	Benign	0.50	T;.;T;T;.
Sift4G	Benign	0.60	T;T;T;T;T
Polyphen		0.030	B;B;B;B;.
Vest4		0.15
MutPred		0.39		Gain of catalytic residue at P534 (P = 0);Gain of catalytic residue at P534 (P = 0);Gain of catalytic residue at P534 (P = 0);Gain of catalytic residue at P534 (P = 0);.;
MVP		0.48
MPC		0.058
ClinPred		0.091	T
GERP RS		2.9
Varity_R		0.24
gMVP		0.20

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: rs552242241; hg19: chr13-108862010;