chr13-108210462-G-A

Variant names:

• chr13-108210462-G-A
• rs2232638
• NM_206937.2:c.807C>T

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.807C>T​(p.Tyr269Tyr) variant causes a synonymous change. The variant allele was found at a frequency of 0.00557 in 1,613,170 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (240 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (223 hom.)
• Consequence: LIG4 NM_206937.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.43
• Publications: 3 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=-0.49).
• BP6: Variant 13-108210462-G-A is Benign according to our data. Variant chr13-108210462-G-A is described in ClinVar as Benign. ClinVar VariationId is 310988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 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.807C>T	p.Tyr269Tyr	synonymous	Exon 3 of 3	NP_996820.1
	LIG4	NM_001352604.2		c.843C>T	p.Tyr281Tyr	synonymous	Exon 3 of 3	NP_001339533.1
	LIG4	NM_001098268.2		c.807C>T	p.Tyr269Tyr	synonymous	Exon 2 of 2	NP_001091738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.807C>T	p.Tyr269Tyr	synonymous	Exon 3 of 3	ENSP00000402030.1
	LIG4	ENST00000405925.2	TSL:1	c.807C>T	p.Tyr269Tyr	synonymous	Exon 2 of 2	ENSP00000385955.1
	LIG4	ENST00000611712.4	TSL:4	c.807C>T	p.Tyr269Tyr	synonymous	Exon 3 of 3	ENSP00000484288.1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4567 AN: 152132 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00766 AC: 1916 AN: 250260 AF XY: 0.00551

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00312

GnomAD4 exome AF: 0.00300 AC: 4380 AN: 1460920 Hom.: 223 Cov.: 34 AF XY: 0.00254 AC XY: 1843 AN XY: 726774

African (AFR) AF: 0.108 AC: 3614 AN: 33470

American (AMR) AF: 0.00512 AC: 229 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52732

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5760

European-Non Finnish (NFE) AF: 0.0000890 AC: 99 AN: 1111814

Other (OTH) AF: 0.00669 AC: 404 AN: 60378

GnomAD4 genome AF: 0.0302 AC: 4602 AN: 152250 Hom.: 240 Cov.: 32 AF XY: 0.0298 AC XY: 2219 AN XY: 74456

African (AFR) AF: 0.105 AC: 4367 AN: 41530

American (AMR) AF: 0.0112 AC: 171 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68020

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0166 Hom.: 73

Bravo AF: 0.0342

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	DNA ligase IV deficiency (3)
-	-	2	not provided (2)
-	-	1	Severe combined immunodeficiency due to DCLRE1C deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.6
DANN	Benign	0.47
PhyloP100		5.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2232638; hg19: chr13-108862810;