rs3731007

Variant names:

• chr19-48123347-G-A
• rs3731007
• NM_000234.3:c.2005-29C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000234.3(LIG1):​c.2005-29C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 1,608,704 control chromosomes in the GnomAD database, including 9,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.15 (2817 hom., cov: 31)
  • Exomes 𝑓: 0.073 (6383 hom.)
• Consequence: LIG1 NM_000234.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.436

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]

ENSG00000269534 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-48123347-G-A is Benign according to our data. Variant chr19-48123347-G-A is described in ClinVar as [Benign]. Clinvar id is 2688333.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG1	NM_000234.3	c.2005-29C>T		intron_variant	Intron 21 of 27	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.2005-29C>T		intron_variant	Intron 21 of 27	1	NM_000234.3	ENSP00000263274.6

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22698 AN: 152008 Hom.: 2818 Cov.: 31

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0884

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0665

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0568

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.103 AC: 25379 AN: 245830 Hom.: 2034 AF XY: 0.101 AC XY: 13518 AN XY: 133598

Gnomad AFR exome AF: 0.340

Gnomad AMR exome AF: 0.0824

Gnomad ASJ exome AF: 0.0871

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.0712

Gnomad NFE exome AF: 0.0586

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.0735 AC: 107037 AN: 1456578 Hom.: 6383 Cov.: 31 AF XY: 0.0751 AC XY: 54414 AN XY: 724842

Gnomad4 AFR exome AF: 0.357

Gnomad4 AMR exome AF: 0.0880

Gnomad4 ASJ exome AF: 0.0852

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0671

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.0963

GnomAD4 genome AF: 0.149 AC: 22713 AN: 152126 Hom.: 2817 Cov.: 31 AF XY: 0.148 AC XY: 11019 AN XY: 74374

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0884

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.0665

Gnomad4 NFE AF: 0.0568

Gnomad4 OTH AF: 0.133

Alfa AF: 0.105 Hom.: 481

Bravo AF: 0.160

Asia WGS AF: 0.166 AC: 578 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.64
BranchPoint Hunter		2.0

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: rs3731007; hg19: chr19-48626604; COSMIC: COSV54390204; COSMIC: COSV54390204;