17-34989496-C-G

Variant names:

• chr17-34989496-C-G
• rs201814781
• NM_013975.4:c.722C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013975.4(LIG3):​c.722C>G​(p.Ser241Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,850 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. S241L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LIG3 NM_013975.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27542877).

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.722C>G	p.Ser241Trp	missense	Exon 4 of 20	NP_039269.2	P49916-1
	LIG3	NM_002311.5		c.722C>G	p.Ser241Trp	missense	Exon 4 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.722C>G	p.Ser241Trp	missense	Exon 4 of 20	ENSP00000367787.3	P49916-1
	LIG3	ENST00000262327.9	TSL:1	c.722C>G	p.Ser241Trp	missense	Exon 4 of 20	ENSP00000262327.4	P49916-2
	LIG3	ENST00000585941.5	TSL:1	c.749C>G	p.Ser250Trp	missense	Exon 4 of 9	ENSP00000468479.1	K7ERZ5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251272 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

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	0.15
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.6
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.39
MutPred		0.22		Loss of phosphorylation at S241 (P = 0.0064)
MVP		0.45
MPC		0.67
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.098
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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: rs201814781; hg19: chr17-33316515;