17-34997363-C-T

Variant names:

• chr17-34997363-C-T
• rs2074518
• NM_013975.4:c.1824-375C>T

Variant summary

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

The NM_013975.4(LIG3):​c.1824-375C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 189,094 control chromosomes in the GnomAD database, including 15,177 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (11930 hom., cov: 32)
  • Exomes 𝑓: 0.40 (3247 hom.)
• Consequence: LIG3 NM_013975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.395
• Publications: 65 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 (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

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.1824-375C>T		intron	N/A	NP_039269.2	P49916-1
	LIG3	NM_002311.5		c.1824-375C>T		intron	N/A	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.1824-375C>T		intron	N/A	ENSP00000367787.3	P49916-1
	LIG3	ENST00000262327.9	TSL:1	c.1824-375C>T		intron	N/A	ENSP00000262327.4	P49916-2
	LIG3	ENST00000858902.1		c.1824-375C>T		intron	N/A	ENSP00000528961.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56397 AN: 151844 Hom.: 11933 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.381

GnomAD4 exome AF: 0.397 AC: 14749 AN: 37132 Hom.: 3247 Cov.: 0 AF XY: 0.396 AC XY: 7888 AN XY: 19938

African (AFR) AF: 0.142 AC: 315 AN: 2214

American (AMR) AF: 0.407 AC: 1581 AN: 3886

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 341 AN: 954

East Asian (EAS) AF: 0.281 AC: 945 AN: 3364

South Asian (SAS) AF: 0.360 AC: 1636 AN: 4550

European-Finnish (FIN) AF: 0.555 AC: 425 AN: 766

Middle Eastern (MID) AF: 0.296 AC: 32 AN: 108

European-Non Finnish (NFE) AF: 0.449 AC: 8791 AN: 19588

Other (OTH) AF: 0.401 AC: 683 AN: 1702

GnomAD4 genome AF: 0.371 AC: 56394 AN: 151962 Hom.: 11930 Cov.: 32 AF XY: 0.376 AC XY: 27950 AN XY: 74260

African (AFR) AF: 0.166 AC: 6869 AN: 41460

American (AMR) AF: 0.400 AC: 6102 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1178 AN: 3466

East Asian (EAS) AF: 0.287 AC: 1485 AN: 5170

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4814

European-Finnish (FIN) AF: 0.570 AC: 6009 AN: 10544

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31625 AN: 67938

Other (OTH) AF: 0.380 AC: 798 AN: 2102

Alfa AF: 0.428 Hom.: 45865

Bravo AF: 0.350

Asia WGS AF: 0.350 AC: 1211 AN: 3464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.71
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2074518; hg19: chr17-33324382;