17-34997659-T-C

Variant names:

• chr17-34997659-T-C
• rs2074517
• NM_013975.4:c.1824-79T>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.1824-79T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,013,882 control chromosomes in the GnomAD database, including 1,706 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 0.025 (141 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1565 hom.)
• Consequence: LIG3 NM_013975.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.26
• Publications: 6 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 (EAS) allele frequency at 95% confidence interval = 0.151 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.1824-79T>C		intron	N/A	NP_039269.2	P49916-1
	LIG3	NM_002311.5		c.1824-79T>C		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.1824-79T>C		intron	N/A	ENSP00000367787.3	P49916-1
	LIG3	ENST00000262327.9	TSL:1	c.1824-79T>C		intron	N/A	ENSP00000262327.4	P49916-2
	LIG3	ENST00000858902.1		c.1824-79T>C		intron	N/A	ENSP00000528961.1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3763 AN: 152152 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0672

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0869

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.0318 AC: 27418 AN: 861612 Hom.: 1565 Cov.: 12 AF XY: 0.0331 AC XY: 14933 AN XY: 450914

African (AFR) AF: 0.00407 AC: 89 AN: 21862

American (AMR) AF: 0.0754 AC: 3257 AN: 43196

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 384 AN: 22258

East Asian (EAS) AF: 0.232 AC: 8484 AN: 36640

South Asian (SAS) AF: 0.0748 AC: 5534 AN: 74014

European-Finnish (FIN) AF: 0.0186 AC: 979 AN: 52764

Middle Eastern (MID) AF: 0.0275 AC: 123 AN: 4470

European-Non Finnish (NFE) AF: 0.0133 AC: 7506 AN: 565872

Other (OTH) AF: 0.0262 AC: 1062 AN: 40536

GnomAD4 genome AF: 0.0247 AC: 3756 AN: 152270 Hom.: 141 Cov.: 32 AF XY: 0.0284 AC XY: 2111 AN XY: 74456

African (AFR) AF: 0.00457 AC: 190 AN: 41562

American (AMR) AF: 0.0672 AC: 1028 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.160 AC: 826 AN: 5166

South Asian (SAS) AF: 0.0857 AC: 413 AN: 4820

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 966 AN: 68016

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0166 Hom.: 22

Bravo AF: 0.0271

Asia WGS AF: 0.0860 AC: 298 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0050
DANN	Benign	0.27
PhyloP100		-3.3
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: rs2074517; hg19: chr17-33324678;