rs4987182

Variant names:

• chr13-108211275-G-A
• rs4987182
• NM_206937.2:c.-7C>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.-7C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,605,472 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (234 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (221 hom.)
• Consequence: LIG4 NM_206937.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.191
• Publications: 5 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=-0.82).
• BP6: Variant 13-108211275-G-A is Benign according to our data. Variant chr13-108211275-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 310996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	NP_996820.1
	LIG4	NM_206937.2	MANE Select	c.-7C>T		5_prime_UTR	Exon 3 of 3	NP_996820.1
	LIG4	NM_001098268.2		c.-7C>T		5_prime_UTR_premature_start_codon_gain	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.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000402030.1
	LIG4	ENST00000405925.2	TSL:1	c.-7C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000385955.1
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.-7C>T		5_prime_UTR	Exon 3 of 3	ENSP00000402030.1

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4523 AN: 152110 Hom.: 231 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

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: 0.000191

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00724 AC: 1775 AN: 245164 AF XY: 0.00533

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00299 AC: 4341 AN: 1453244 Hom.: 221 Cov.: 30 AF XY: 0.00253 AC XY: 1827 AN XY: 723420

African (AFR) AF: 0.107 AC: 3564 AN: 33392

American (AMR) AF: 0.00510 AC: 228 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51410

Middle Eastern (MID) AF: 0.00396 AC: 22 AN: 5554

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1106168

Other (OTH) AF: 0.00663 AC: 399 AN: 60176

GnomAD4 genome AF: 0.0299 AC: 4558 AN: 152228 Hom.: 234 Cov.: 32 AF XY: 0.0295 AC XY: 2197 AN XY: 74440

African (AFR) AF: 0.104 AC: 4326 AN: 41532

American (AMR) AF: 0.0110 AC: 169 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68006

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

Alfa AF: 0.0149 Hom.: 62

Bravo AF: 0.0338

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000238

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	DNA ligase IV deficiency (2)
-	-	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	-0.82
CADD	Benign	1.4
DANN	Benign	0.56
PhyloP100		-0.19
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4987182; hg19: chr13-108863623;