rs2074522

Variant names:

• chr17-35002629-G-A
• rs2074522
• NM_013975.4:c.2675-39G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-35002629-G-A
• chr17-35002629-G-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.2675-39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 1,598,088 control chromosomes in the GnomAD database, including 8,204 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 0.090 (690 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7514 hom.)
• Consequence: LIG3 NM_013975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341
• Publications: 8 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.132 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.2675-39G>A		intron	N/A	NP_039269.2	P49916-1
	LIG3	NM_002311.5		c.2675-39G>A		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.2675-39G>A		intron	N/A	ENSP00000367787.3	P49916-1
	LIG3	ENST00000262327.9	TSL:1	c.2675-39G>A		intron	N/A	ENSP00000262327.4	P49916-2
	LIG3	ENST00000858902.1		c.2675-39G>A		intron	N/A	ENSP00000528961.1

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 13728 AN: 152124 Hom.: 691 Cov.: 32

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0490

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0916

GnomAD2 exomes AF: 0.103 AC: 23446 AN: 227626 AF XY: 0.108

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.0819

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.0382

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0979 AC: 141497 AN: 1445846 Hom.: 7514 Cov.: 31 AF XY: 0.100 AC XY: 71928 AN XY: 718186

African (AFR) AF: 0.0567 AC: 1875 AN: 33046

American (AMR) AF: 0.0808 AC: 3447 AN: 42638

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4610 AN: 25744

East Asian (EAS) AF: 0.0453 AC: 1767 AN: 39038

South Asian (SAS) AF: 0.153 AC: 12860 AN: 83962

European-Finnish (FIN) AF: 0.128 AC: 6686 AN: 52340

Middle Eastern (MID) AF: 0.123 AC: 551 AN: 4490

European-Non Finnish (NFE) AF: 0.0940 AC: 103806 AN: 1104860

Other (OTH) AF: 0.0987 AC: 5895 AN: 59728

GnomAD4 genome AF: 0.0901 AC: 13722 AN: 152242 Hom.: 690 Cov.: 32 AF XY: 0.0918 AC XY: 6835 AN XY: 74436

African (AFR) AF: 0.0578 AC: 2402 AN: 41554

American (AMR) AF: 0.0783 AC: 1198 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 648 AN: 3472

East Asian (EAS) AF: 0.0487 AC: 252 AN: 5172

South Asian (SAS) AF: 0.140 AC: 678 AN: 4826

European-Finnish (FIN) AF: 0.136 AC: 1437 AN: 10592

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.100 AC: 6821 AN: 68014

Other (OTH) AF: 0.0925 AC: 195 AN: 2108

Alfa AF: 0.109 Hom.: 181

Bravo AF: 0.0807

Asia WGS AF: 0.118 AC: 414 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.61
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2074522; hg19: chr17-33329648;