Variant chr17-34989564-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_013975.4(LIG3):c.790C>T(p.Arg264Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

LIG3
NM_013975.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG3	NM_013975.4 linkuse as main transcript	c.790C>T	p.Arg264Trp	missense_variant	4/20	ENST00000378526.9	NP_039269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG3	ENST00000378526.9 linkuse as main transcript	c.790C>T	p.Arg264Trp	missense_variant	4/20	1	NM_013975.4	ENSP00000367787	P1	P49916-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251470

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.790C>T (p.R264W) alteration is located in exon 4 (coding exon 3) of the LIG3 gene. This alteration results from a C to T substitution at nucleotide position 790, causing the arginine (R) at amino acid position 264 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;T;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.080

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.5

M;.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.5

D;.;D;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

D;.;D;.

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.87

MVP

0.30

MPC

0.95

ClinPred

0.95

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over