chr17-34986111-G-T

Variant names:

• chr17-34986111-G-T
• rs202243099
• NM_013975.4:c.671G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 3 publications found

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]

LIG3 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 20 (mngie type)

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20061013).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013975.4. 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
	LIG3	NM_013975.4	MANE Select	c.671G>T	p.Arg224Leu	missense	Exon 3 of 20	NP_039269.2	P49916-1
	LIG3	NM_002311.5		c.671G>T	p.Arg224Leu	missense	Exon 3 of 20	NP_002302.2	P49916-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG3	ENST00000378526.9	TSL:1 MANE Select	c.671G>T	p.Arg224Leu	missense	Exon 3 of 20	ENSP00000367787.3	P49916-1
	LIG3	ENST00000262327.9	TSL:1	c.671G>T	p.Arg224Leu	missense	Exon 3 of 20	ENSP00000262327.4	P49916-2
	LIG3	ENST00000585941.5	TSL:1	c.698G>T	p.Arg233Leu	missense	Exon 3 of 9	ENSP00000468479.1	K7ERZ5

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

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.053
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.21	T
Sift4G	Benign	0.14	T
Polyphen		0.023	B
Vest4		0.33
MutPred		0.27		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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs202243099; hg19: chr17-33313130; COSMIC: COSV99253120;