NM_206937.2:c.-102+431T>C

Variant names:

• chr13-108215053-A-G
• rs3093739
• NM_206937.2:c.-102+431T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_206937.2(LIG4):​c.-102+431T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.092 (311 hom., cov: 9)
• Consequence: LIG4 NM_206937.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.60
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 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.-102+431T>C		intron	N/A	NP_996820.1
	LIG4	NM_001352604.2		c.-94+271T>C		intron	N/A	NP_001339533.1
	LIG4	NM_001098268.2		c.-29+3109T>C		intron	N/A	NP_001091738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG4	ENST00000442234.6	TSL:1 MANE Select	c.-102+431T>C		intron	N/A	ENSP00000402030.1
	LIG4	ENST00000405925.2	TSL:1	c.-29+3109T>C		intron	N/A	ENSP00000385955.1
	LIG4	ENST00000611712.4	TSL:4	c.-298-246T>C		intron	N/A	ENSP00000484288.1

Frequencies

GnomAD3 genomes AF: 0.0919 AC: 4990 AN: 54290 Hom.: 311 Cov.: 9

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0837

Gnomad FIN AF: 0.0988

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.0899

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0918 AC: 4990 AN: 54330 Hom.: 311 Cov.: 9 AF XY: 0.0916 AC XY: 2293 AN XY: 25024

African (AFR) AF: 0.0774 AC: 974 AN: 12582

American (AMR) AF: 0.103 AC: 486 AN: 4708

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 221 AN: 1584

East Asian (EAS) AF: 0.118 AC: 180 AN: 1522

South Asian (SAS) AF: 0.0831 AC: 74 AN: 890

European-Finnish (FIN) AF: 0.0988 AC: 292 AN: 2956

Middle Eastern (MID) AF: 0.103 AC: 14 AN: 136

European-Non Finnish (NFE) AF: 0.0909 AC: 2621 AN: 28842

Other (OTH) AF: 0.0908 AC: 63 AN: 694

Alfa AF: 0.114 Hom.: 226

Bravo AF: 0.130

Asia WGS AF: 0.103 AC: 332 AN: 3234

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.1
DANN	Benign	0.19
PhyloP100		-4.6
PromoterAI		-0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs3093739; hg19: chr13-108867401;