rs1805388

Variant names:

• chr13-108211243-G-A
• rs1805388
• NM_206937.2:c.26C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-108211243-G-A
• chr13-108211243-G-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.26C>T​(p.Thr9Ile) variant causes a missense change. The variant allele was found at a frequency of 0.165 in 1,610,136 control chromosomes in the GnomAD database, including 23,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T9S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2252 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21217 hom.)
• Consequence: LIG4 NM_206937.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 4.05
• Publications: 114 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=0.0015589893).
• BP6: Variant 13-108211243-G-A is Benign according to our data. Variant chr13-108211243-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	NM_206937.2	MANE Select	c.26C>T	p.Thr9Ile	missense	Exon 3 of 3	NP_996820.1	P49917
	LIG4	NM_001098268.2		c.26C>T	p.Thr9Ile	missense	Exon 2 of 2	NP_001091738.1	P49917
	LIG4	NM_001352598.2		c.26C>T	p.Thr9Ile	missense	Exon 4 of 4	NP_001339527.1	P49917

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.26C>T	p.Thr9Ile	missense	Exon 3 of 3	ENSP00000402030.1	P49917
	LIG4	ENST00000405925.2	TSL:1	c.26C>T	p.Thr9Ile	missense	Exon 2 of 2	ENSP00000385955.1	P49917
	LIG4	ENST00000611712.4	TSL:4	c.26C>T	p.Thr9Ile	missense	Exon 3 of 3	ENSP00000484288.1	P49917

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24709 AN: 151982 Hom.: 2250 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.0977

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.0892

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.177 AC: 43666 AN: 247176 AF XY: 0.170

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.0859

Gnomad EAS exome AF: 0.227

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.165 AC: 240295 AN: 1458036 Hom.: 21217 Cov.: 34 AF XY: 0.162 AC XY: 117597 AN XY: 725348

African (AFR) AF: 0.102 AC: 3405 AN: 33468

American (AMR) AF: 0.231 AC: 10341 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 2335 AN: 26122

East Asian (EAS) AF: 0.166 AC: 6570 AN: 39660

South Asian (SAS) AF: 0.0865 AC: 7460 AN: 86194

European-Finnish (FIN) AF: 0.280 AC: 14601 AN: 52146

Middle Eastern (MID) AF: 0.0880 AC: 502 AN: 5704

European-Non Finnish (NFE) AF: 0.168 AC: 185968 AN: 1109762

Other (OTH) AF: 0.151 AC: 9113 AN: 60284

GnomAD4 genome AF: 0.163 AC: 24721 AN: 152100 Hom.: 2252 Cov.: 32 AF XY: 0.168 AC XY: 12458 AN XY: 74332

African (AFR) AF: 0.104 AC: 4318 AN: 41526

American (AMR) AF: 0.205 AC: 3131 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0977 AC: 339 AN: 3470

East Asian (EAS) AF: 0.219 AC: 1133 AN: 5180

South Asian (SAS) AF: 0.0895 AC: 431 AN: 4818

European-Finnish (FIN) AF: 0.295 AC: 3116 AN: 10550

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11687 AN: 67970

Other (OTH) AF: 0.132 AC: 279 AN: 2110

Alfa AF: 0.162 Hom.: 9012

Bravo AF: 0.154

TwinsUK AF: 0.169 AC: 628

ALSPAC AF: 0.174 AC: 670

ESP6500AA AF: 0.103 AC: 450

ESP6500EA AF: 0.155 AC: 1310

ExAC AF: 0.169 AC: 20477

Asia WGS AF: 0.152 AC: 531 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.156

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	DNA ligase IV deficiency (3)
-	-	2	not provided (3)
-	-	1	Severe combined immunodeficiency due to DCLRE1C deficiency (1)
-	-	-	Multiple myeloma, resistance to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.093
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.073
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		0.52	P
Vest4		0.089
MPC		0.059
ClinPred		0.030	T
GERP RS		4.1
Varity_R		0.16
gMVP		0.45
Mutation Taster		=97/3	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: rs1805388; hg19: chr13-108863591; COSMIC: COSV63597095;