rs13436

chr19-48117779-C-Gchr19-48117779-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000234.3(LIG1):c.2442G>C(p.Ala814=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,611,088 control chromosomes in the GnomAD database, including 162,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A814A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17579 hom., cov: 34)
  • Exomes 𝑓: 0.44 (145279 hom.)
• Consequence: LIG1 NM_000234.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.688

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-48117779-C-G is Benign according to our data. Variant chr19-48117779-C-G is described in ClinVar as [Benign]. Clinvar id is 403033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.688 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG1	NM_000234.3	c.2442G>C	p.Ala814=	splice_region_variant, synonymous_variant	26/28	ENST00000263274.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG1	ENST00000263274.12	c.2442G>C	p.Ala814=	splice_region_variant, synonymous_variant	26/28	1	NM_000234.3	P4

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72135 AN: 152012 Hom.: 17560 Cov.: 34

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.479

GnomAD3 exomes AF: 0.463 AC: 113343 AN: 244628 Hom.: 27359 AF XY: 0.464 AC XY: 61256 AN XY: 132114

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.754

Gnomad SAS exome AF: 0.476

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.441 AC: 643367 AN: 1458958 Hom.: 145279 Cov.: 46 AF XY: 0.442 AC XY: 320384 AN XY: 725416

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.769

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.424

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.475 AC: 72196 AN: 152130 Hom.: 17579 Cov.: 34 AF XY: 0.475 AC XY: 35353 AN XY: 74384

Gnomad4 AFR AF: 0.544

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.750

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.481

Alfa AF: 0.400 Hom.: 3715

Bravo AF: 0.474

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 60% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	8.5
Dann	Benign	0.78

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: rs13436; hg19: chr19-48621036; COSMIC: COSV54392236; COSMIC: COSV54392236;