rs3093740

Positions:

• chr13-108214465-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_206937.2(LIG4):​c.-29+73A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 152,144 control chromosomes in the GnomAD database, including 586 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.053 (586 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (0 hom.)
• Consequence: LIG4 NM_206937.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.795

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG4	NM_206937.2	c.-29+73A>C		intron_variant		ENST00000442234.6	NP_996820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6	c.-29+73A>C		intron_variant		1	NM_206937.2	ENSP00000402030	P1

Frequencies

GnomAD3 genomes AF: 0.0524 AC: 7963 AN: 151924 Hom.: 584 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.0398

GnomAD4 exome AF: 0.00980 AC: 1 AN: 102 Hom.: 0 AF XY: 0.0152 AC XY: 1 AN XY: 66

Gnomad4 AFR exome AF: 0.250

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0526 AC: 7998 AN: 152042 Hom.: 586 Cov.: 32 AF XY: 0.0512 AC XY: 3804 AN XY: 74318

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0242

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00611

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0518 Hom.: 105

Bravo AF: 0.0586

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.43

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: rs3093740; hg19: chr13-108866813;