rs3730849

Positions:

• chr19-48165538-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000234.3(LIG1):​c.17+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,596,792 control chromosomes in the GnomAD database, including 111,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8109 hom., cov: 31)
  • Exomes 𝑓: 0.37 (103020 hom.)
• Consequence: LIG1 NM_000234.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.22

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-48165538-G-A is Benign according to our data. Variant chr19-48165538-G-A is described in ClinVar as [Benign]. Clinvar id is 403038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG1	NM_000234.3	c.17+12C>T		intron_variant		ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.17+12C>T		intron_variant		1	NM_000234.3	ENSP00000263274	P4

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45850 AN: 151714 Hom.: 8106 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.359 AC: 90308 AN: 251440 Hom.: 17560 AF XY: 0.363 AC XY: 49336 AN XY: 135898

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.330

Gnomad EAS exome AF: 0.574

Gnomad SAS exome AF: 0.317

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.371 AC: 535969 AN: 1444960 Hom.: 103020 Cov.: 30 AF XY: 0.370 AC XY: 266516 AN XY: 719868

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.328

Gnomad4 EAS exome AF: 0.558

Gnomad4 SAS exome AF: 0.311

Gnomad4 FIN exome AF: 0.419

Gnomad4 NFE exome AF: 0.380

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.302 AC: 45867 AN: 151832 Hom.: 8109 Cov.: 31 AF XY: 0.305 AC XY: 22647 AN XY: 74164

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.548

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.330

Alfa AF: 0.339 Hom.: 2077

Bravo AF: 0.287

Asia WGS AF: 0.435 AC: 1510 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 57% of patients studied by a panel of primary immunodeficiencies. Number of patients: 55. Only high quality variants are reported. -

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	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.066
DANN	Benign	0.57

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

Other links and lift over

dbSNP: rs3730849; hg19: chr19-48668795;