rs3731003

Positions:

chr19-48128001-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000263274.12(LIG1):c.1841C>T(p.Thr614Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,120 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.011 ( 29 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 27 hom. )

Consequence

LIG1
ENST00000263274.12 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.88

Variant links:

Genes affected

LIG1 (HGNC:6598): (DNA ligase 1) This gene encodes a member of the ATP-dependent DNA ligase protein family. The encoded protein functions in DNA replication, recombination, and the base excision repair process. Mutations in this gene that lead to DNA ligase I deficiency result in immunodeficiency and increased sensitivity to DNA-damaging agents. Disruption of this gene may also be associated with a variety of cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

LIG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008318454).

BP6

Variant 19-48128001-G-A is Benign according to our data. Variant chr19-48128001-G-A is described in ClinVar as [Benign]. Clinvar id is 1164605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1729/152300) while in subpopulation AFR AF= 0.0393 (1634/41544). AF 95% confidence interval is 0.0377. There are 29 homozygotes in gnomad4. There are 809 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG1	NM_000234.3 linkuse as main transcript	c.1841C>T	p.Thr614Ile	missense_variant	20/28	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12 linkuse as main transcript	c.1841C>T	p.Thr614Ile	missense_variant	20/28	1	NM_000234.3	ENSP00000263274	P4	P18858-1

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1716

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0391

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00812

GnomAD3 exomes

AF:

0.00290

AC:

729

AN:

251492

Hom.:

AF XY:

0.00207

AC XY:

281

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00107

AC:

1571

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000870

AC XY:

633

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0378

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.0114

AC:

1729

AN:

152300

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

809

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0393

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.0133

ESP6500AA

AF:

0.0409

AC:

180

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00348

AC:

422

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

LIG1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;.;.;.

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.88

D;D;D;D

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.1

M;.;.;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.3

D;D;D;.

REVEL

Benign

0.080

Sift

Uncertain

0.024

D;D;D;.

Sift4G

Uncertain

0.048

D;D;D;T

Polyphen

0.85

P;P;.;.

Vest4

0.17

MVP

0.50

MPC

0.65

ClinPred

0.047

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.16

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