rs3136025

Variant names:

• chr17-35002030-G-A
• rs3136025
• NM_013975.4:c.2600G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-35002030-G-A
• chr17-35002030-G-C

Variant summary

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

The NM_013975.4(LIG3):​c.2600G>A​(p.Arg867His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00485 in 1,609,630 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (168 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (162 hom.)
• Consequence: LIG3 NM_013975.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.880
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017380416).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG3	NM_013975.4	c.2600G>A	p.Arg867His	missense_variant	Exon 18 of 20	ENST00000378526.9	NP_039269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG3	ENST00000378526.9	c.2600G>A	p.Arg867His	missense_variant	Exon 18 of 20	1	NM_013975.4	ENSP00000367787.3
LIG3	ENST00000262327.9	c.2600G>A	p.Arg867His	missense_variant	Exon 18 of 20	1		ENSP00000262327.4
LIG3	ENST00000593099.5	n.2453G>A		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3829 AN: 152010 Hom.: 169 Cov.: 32

Gnomad AFR AF: 0.0869

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.00679 AC: 1676 AN: 246728 AF XY: 0.00481

Gnomad AFR exome AF: 0.0898

Gnomad AMR exome AF: 0.00521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00468

GnomAD4 exome AF: 0.00272 AC: 3971 AN: 1457502 Hom.: 162 Cov.: 31 AF XY: 0.00232 AC XY: 1685 AN XY: 725012

African (AFR) AF: 0.0927 AC: 3081 AN: 33226

American (AMR) AF: 0.00606 AC: 264 AN: 43592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39560

South Asian (SAS) AF: 0.000409 AC: 35 AN: 85550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00296 AC: 17 AN: 5746

European-Non Finnish (NFE) AF: 0.000166 AC: 184 AN: 1110272

Other (OTH) AF: 0.00646 AC: 389 AN: 60230

GnomAD4 genome AF: 0.0252 AC: 3837 AN: 152128 Hom.: 168 Cov.: 32 AF XY: 0.0237 AC XY: 1763 AN XY: 74368

African (AFR) AF: 0.0868 AC: 3601 AN: 41482

American (AMR) AF: 0.0111 AC: 169 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68000

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0194 Hom.: 120

Bravo AF: 0.0297

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0860 AC: 379

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00828 AC: 1005

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.53
DANN	Benign	0.67
DEOGEN2	Uncertain	0.44	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.60	N;N
PhyloP100		-0.88
PrimateAI	Benign	0.17	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.037
Sift	Benign	0.29	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	B;.
Vest4		0.040
MVP		0.040
MPC		0.33
ClinPred		0.00073	T
GERP RS		-7.8
Varity_R		0.020
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3136025; hg19: chr17-33329049; COSMIC: COSV52006804; COSMIC: COSV52006804;