rs1003918

Variant names:

• chr17-35005158-G-A
• rs1003918
• NM_013975.4:c.*652G>A

Variant summary

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

The NM_013975.4(LIG3):​c.*652G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 364,218 control chromosomes in the GnomAD database, including 32,137 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 0.38 (12130 hom., cov: 32)
  • Exomes 𝑓: 0.43 (20007 hom.)
• Consequence: LIG3 NM_013975.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158
• Publications: 30 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG3	NM_013975.4	c.*652G>A		3_prime_UTR_variant	Exon 20 of 20	ENST00000378526.9	NP_039269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG3	ENST00000378526.9	c.*652G>A		3_prime_UTR_variant	Exon 20 of 20	1	NM_013975.4	ENSP00000367787.3

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57680 AN: 151888 Hom.: 12130 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.426 AC: 90462 AN: 212210 Hom.: 20007 Cov.: 0 AF XY: 0.419 AC XY: 49071 AN XY: 117232

African (AFR) AF: 0.196 AC: 1092 AN: 5558

American (AMR) AF: 0.408 AC: 5068 AN: 12410

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1664 AN: 4828

East Asian (EAS) AF: 0.297 AC: 2584 AN: 8698

South Asian (SAS) AF: 0.358 AC: 15131 AN: 42250

European-Finnish (FIN) AF: 0.563 AC: 5060 AN: 8984

Middle Eastern (MID) AF: 0.356 AC: 829 AN: 2328

European-Non Finnish (NFE) AF: 0.467 AC: 54603 AN: 116854

Other (OTH) AF: 0.430 AC: 4431 AN: 10300

GnomAD4 genome AF: 0.379 AC: 57682 AN: 152008 Hom.: 12130 Cov.: 32 AF XY: 0.385 AC XY: 28626 AN XY: 74314

African (AFR) AF: 0.200 AC: 8303 AN: 41464

American (AMR) AF: 0.395 AC: 6026 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1179 AN: 3472

East Asian (EAS) AF: 0.287 AC: 1480 AN: 5156

South Asian (SAS) AF: 0.356 AC: 1715 AN: 4812

European-Finnish (FIN) AF: 0.570 AC: 6019 AN: 10562

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

European-Non Finnish (NFE) AF: 0.465 AC: 31596 AN: 67958

Other (OTH) AF: 0.385 AC: 813 AN: 2112

Alfa AF: 0.428 Hom.: 55949

Bravo AF: 0.359

Asia WGS AF: 0.348 AC: 1209 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.3
DANN	Benign	0.72
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1003918; hg19: chr17-33332177;