rs554949695

Positions:

• chr13-108211235-A-C
• chr13-108211235-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_206937.2(LIG4):​c.34T>G​(p.Ser12Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S12T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIG4 NM_206937.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08534449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG4	NM_206937.2	c.34T>G	p.Ser12Ala	missense_variant	3/3	ENST00000442234.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG4	ENST00000442234.6	c.34T>G	p.Ser12Ala	missense_variant	3/3	1	NM_206937.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460662 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726602

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DNA ligase IV deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with LIG4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with alanine at codon 12 of the LIG4 protein (p.Ser12Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.065	T;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.55	.;.;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;L;L;L
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Benign	0.18
Sift	Benign	0.25	T;.;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.070
MutPred		0.32		Gain of catalytic residue at F16 (P = 0.0075);Gain of catalytic residue at F16 (P = 0.0075);Gain of catalytic residue at F16 (P = 0.0075);Gain of catalytic residue at F16 (P = 0.0075);
MVP		0.20
MPC		0.044
ClinPred		0.37	T
GERP RS		2.0
Varity_R		0.11
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs554949695; hg19: chr13-108863583;