rs1805384

Positions:

• chr13-108211333-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_206937.2(LIG4):​c.-28-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,142,904 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (221 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (198 hom.)
• Consequence: LIG4 NM_206937.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.104

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-108211333-A-G is Benign according to our data. Variant chr13-108211333-A-G is described in ClinVar as [Benign]. Clinvar id is 1247962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG4	NM_206937.2	c.-28-37T>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.-28-37T>C		intron_variant		1	NM_206937.2	ENSP00000402030.1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5306 AN: 152150 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.00961 AC: 9519 AN: 990636 Hom.: 198 Cov.: 13 AF XY: 0.00955 AC XY: 4868 AN XY: 509788

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00168

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.00299

Gnomad4 NFE exome AF: 0.00543

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0349 AC: 5310 AN: 152268 Hom.: 221 Cov.: 32 AF XY: 0.0339 AC XY: 2523 AN XY: 74450

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0253 Hom.: 22

Bravo AF: 0.0389

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805384; hg19: chr13-108863681;