rs1805384

Variant names:

• chr13-108211333-A-G
• rs1805384
• NM_206937.2:c.-28-37T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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: Benign. The variant received -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 VariationId 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.

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.-28-37T>C		intron	N/A	NP_996820.1
	LIG4	NM_001352604.2		c.89-117T>C		intron	N/A	NP_001339533.1
	LIG4	NM_001098268.2		c.-28-37T>C		intron	N/A	NP_001091738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.-28-37T>C		intron	N/A	ENSP00000402030.1
	LIG4	ENST00000405925.2	TSL:1	c.-28-37T>C		intron	N/A	ENSP00000385955.1
	LIG4	ENST00000611712.4	TSL:4	c.-28-37T>C		intron	N/A	ENSP00000484288.1

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

African (AFR) AF: 0.104 AC: 2495 AN: 24044

American (AMR) AF: 0.0134 AC: 528 AN: 39426

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 471 AN: 23124

East Asian (EAS) AF: 0.00168 AC: 59 AN: 35212

South Asian (SAS) AF: 0.0159 AC: 1174 AN: 73804

European-Finnish (FIN) AF: 0.00299 AC: 123 AN: 41100

Middle Eastern (MID) AF: 0.0379 AC: 134 AN: 3538

European-Non Finnish (NFE) AF: 0.00543 AC: 3834 AN: 705716

Other (OTH) AF: 0.0157 AC: 701 AN: 44672

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

African (AFR) AF: 0.101 AC: 4211 AN: 41526

American (AMR) AF: 0.0256 AC: 392 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5190

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10624

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00622 AC: 423 AN: 68012

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0274 Hom.: 24

Bravo AF: 0.0389

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.61
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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: rs1805384; hg19: chr13-108863681;