chr17-34986111-G-T

Position:

• chr17-34986111-G-T

Variant summary

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

The NM_013975.4(LIG3):​c.671G>T​(p.Arg224Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R224W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LIG3 NM_013975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.00

Genes affected

LIG3 (HGNC:6600): (DNA ligase 3) This gene is a member of the DNA ligase family. Each member of this family encodes a protein that catalyzes the joining of DNA ends but they each have a distinct role in DNA metabolism. The protein encoded by this gene is involved in excision repair and is located in both the mitochondria and nucleus, with translation initiation from the upstream start codon allowing for transport to the mitochondria and translation initiation from a downstream start codon allowing for transport to the nucleus. Additionally, alternate transcriptional splice variants, encoding different isoforms, have been characterized. [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=0.20061013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG3	NM_013975.4	c.671G>T	p.Arg224Leu	missense_variant	3/20	ENST00000378526.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG3	ENST00000378526.9	c.671G>T	p.Arg224Leu	missense_variant	3/20	1	NM_013975.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000597

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.671G>T (p.R224L) alteration is located in exon 3 (coding exon 2) of the LIG3 gene. This alteration results from a G to T substitution at nucleotide position 671, causing the arginine (R) at amino acid position 224 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;T
Eigen	Benign	-0.053
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.21	T;.;T;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.023	B;.;.;.
Vest4		0.33
MutPred		0.27		Loss of solvent accessibility (P = 0.0052);.;Loss of solvent accessibility (P = 0.0052);.;
MVP		0.60
MPC		0.34
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202243099; hg19: chr17-33313130; COSMIC: COSV99253120;