13-108209471-C-T

Variant names:

• chr13-108209471-C-T
• rs61731910
• NM_206937.2:c.1798G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_206937.2(LIG4):​c.1798G>A​(p.Glu600Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00107 in 1,614,084 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E600E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (8 hom.)
• Consequence: LIG4 NM_206937.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.54
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039753914).
• BP6: Variant 13-108209471-C-T is Benign according to our data. Variant chr13-108209471-C-T is described in ClinVar as Benign. ClinVar VariationId is 211373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00547 (832/152210) while in subpopulation AFR AF = 0.0186 (772/41530). AF 95% confidence interval is 0.0175. There are 9 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1798G>A	p.Glu600Lys	missense	Exon 3 of 3	NP_996820.1	P49917
	LIG4	NM_001352604.2		c.1834G>A	p.Glu612Lys	missense	Exon 3 of 3	NP_001339533.1
	LIG4	NM_001098268.2		c.1798G>A	p.Glu600Lys	missense	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.1798G>A	p.Glu600Lys	missense	Exon 3 of 3	ENSP00000402030.1	P49917
	LIG4	ENST00000405925.2	TSL:1	c.1798G>A	p.Glu600Lys	missense	Exon 2 of 2	ENSP00000385955.1	P49917
	LIG4	ENST00000611712.4	TSL:4	c.1798G>A	p.Glu600Lys	missense	Exon 3 of 3	ENSP00000484288.1	P49917

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 827 AN: 152092 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00164 AC: 413 AN: 251460 AF XY: 0.00116

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000607 AC: 887 AN: 1461874 Hom.: 8 Cov.: 33 AF XY: 0.000487 AC XY: 354 AN XY: 727234

African (AFR) AF: 0.0206 AC: 690 AN: 33480

American (AMR) AF: 0.00165 AC: 74 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112002

Other (OTH) AF: 0.00151 AC: 91 AN: 60396

GnomAD4 genome AF: 0.00547 AC: 832 AN: 152210 Hom.: 9 Cov.: 32 AF XY: 0.00551 AC XY: 410 AN XY: 74430

African (AFR) AF: 0.0186 AC: 772 AN: 41530

American (AMR) AF: 0.00301 AC: 46 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68000

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00240 Hom.: 5

Bravo AF: 0.00654

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.083
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.076	T
Sift4G	Benign	0.062	T
Polyphen		0.26	B
Vest4		0.42
MVP		0.46
MPC		0.059
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.45
Mutation Taster		=99/1	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: rs61731910; hg19: chr13-108861819;