17-34988426-G-A

Variant names:

• chr17-34988426-G-A
• rs3135974
• NM_013975.4:c.692-1040G>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.692-1040G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 151,954 control chromosomes in the GnomAD database, including 980 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 0.11 (980 hom., cov: 32)
• Consequence: LIG3 NM_013975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.122
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG3	NM_013975.4	MANE Select	c.692-1040G>A		intron	N/A	NP_039269.2
	LIG3	NM_002311.5		c.692-1040G>A		intron	N/A	NP_002302.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG3	ENST00000378526.9	TSL:1 MANE Select	c.692-1040G>A		intron	N/A	ENSP00000367787.3
	LIG3	ENST00000262327.9	TSL:1	c.692-1040G>A		intron	N/A	ENSP00000262327.4
	LIG3	ENST00000585941.5	TSL:1	c.719-1040G>A		intron	N/A	ENSP00000468479.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17177 AN: 151836 Hom.: 979 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0694

Gnomad AMR AF: 0.0883

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0489

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.114

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.113 AC: 17195 AN: 151954 Hom.: 980 Cov.: 32 AF XY: 0.114 AC XY: 8480 AN XY: 74276

African (AFR) AF: 0.136 AC: 5641 AN: 41424

American (AMR) AF: 0.0882 AC: 1346 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3472

East Asian (EAS) AF: 0.0488 AC: 252 AN: 5160

South Asian (SAS) AF: 0.142 AC: 681 AN: 4804

European-Finnish (FIN) AF: 0.136 AC: 1438 AN: 10554

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6849 AN: 67966

Other (OTH) AF: 0.115 AC: 241 AN: 2104

Alfa AF: 0.0815 Hom.: 133

Bravo AF: 0.107

Asia WGS AF: 0.122 AC: 429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-0.12
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: rs3135974; hg19: chr17-33315445;