rs3731008

chr19-48123293-C-Achr19-48123293-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000234.3(LIG1):c.2030G>T(p.Arg677Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,613,744 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R677W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.403

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013813436).
• BP6: Variant 19-48123293-C-A is Benign according to our data. Variant chr19-48123293-C-A is described in ClinVar as [Benign]. Clinvar id is 788029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG1	NM_000234.3	c.2030G>T	p.Arg677Leu	missense_variant	22/28	ENST00000263274.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG1	ENST00000263274.12	c.2030G>T	p.Arg677Leu	missense_variant	22/28	1	NM_000234.3	P4
	ENST00000596563.5	n.176+2034C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152058 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00120 AC: 300 AN: 250862 Hom.: 2 AF XY: 0.000818 AC XY: 111 AN XY: 135726

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000432 AC: 632 AN: 1461568 Hom.: 5 Cov.: 32 AF XY: 0.000374 AC XY: 272 AN XY: 727098

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152176 Hom.: 8 Cov.: 31 AF XY: 0.00367 AC XY: 273 AN XY: 74396

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00120 Hom.: 4

Bravo AF: 0.00454

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00159 AC: 193

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	LIG1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

LIG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2024

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	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.014	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.7	L;.;.;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D;D;D;.
REVEL	Benign	0.29
Sift	Uncertain	0.025	D;D;D;.
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.067	B;B;.;.
Vest4		0.56
MVP		0.50
MPC		0.37
ClinPred		0.021	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs3731008; hg19: chr19-48626550; COSMIC: COSV105033937; COSMIC: COSV105033937;