chr13-108208529-AG-A

Variant names:

• chr13-108208529-AG-A
• rs551263548
• NM_206937.2:c.*3delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_206937.2(LIG4):​c.*3delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,591,694 control chromosomes in the GnomAD database, including 50 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (44 hom.)
• Consequence: LIG4 NM_206937.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.275
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• 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 -16 ACMG points.

• BP6: Variant 13-108208529-AG-A is Benign according to our data. Variant chr13-108208529-AG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00582 (886/152336) while in subpopulation NFE AF = 0.00783 (533/68032). AF 95% confidence interval is 0.00728. There are 6 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	NM_206937.2	MANE Select	c.*3delC		3_prime_UTR	Exon 3 of 3	NP_996820.1	P49917
	LIG4	NM_001352604.2		c.*3delC		3_prime_UTR	Exon 3 of 3	NP_001339533.1
	LIG4	NM_001098268.2		c.*3delC		3_prime_UTR	Exon 2 of 2	NP_001091738.1	P49917

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.*3delC		3_prime_UTR	Exon 3 of 3	ENSP00000402030.1	P49917
	LIG4	ENST00000405925.2	TSL:1	c.*3delC		3_prime_UTR	Exon 2 of 2	ENSP00000385955.1	P49917
	LIG4	ENST00000611712.4	TSL:4	c.*3delC		3_prime_UTR	Exon 3 of 3	ENSP00000484288.1	P49917

Frequencies

GnomAD3 genomes AF: 0.00582 AC: 886 AN: 152218 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00565 AC: 1394 AN: 246836 AF XY: 0.00572

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00191

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.00521 AC: 7502 AN: 1439358 Hom.: 44 Cov.: 28 AF XY: 0.00529 AC XY: 3796 AN XY: 717292

African (AFR) AF: 0.000667 AC: 22 AN: 32966

American (AMR) AF: 0.00292 AC: 130 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00243 AC: 63 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.000316 AC: 27 AN: 85482

European-Finnish (FIN) AF: 0.0162 AC: 863 AN: 53128

Middle Eastern (MID) AF: 0.00349 AC: 20 AN: 5726

European-Non Finnish (NFE) AF: 0.00555 AC: 6067 AN: 1092468

Other (OTH) AF: 0.00520 AC: 310 AN: 59618

GnomAD4 genome AF: 0.00582 AC: 886 AN: 152336 Hom.: 6 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74500

African (AFR) AF: 0.000914 AC: 38 AN: 41588

American (AMR) AF: 0.00425 AC: 65 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00783 AC: 533 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00758 Hom.: 1

Bravo AF: 0.00476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	DNA ligase IV deficiency (1)
-	-	1	LIG4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs551263548; hg19: chr13-108860877;