rs20581

Positions:

• chr19-48119170-A-G

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.2406T>C​(p.Asp802=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 1,581,660 control chromosomes in the GnomAD database, including 259,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32670 hom., cov: 32)
  • Exomes 𝑓: 0.56 (226941 hom.)
• Consequence: LIG1 NM_000234.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.84

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 19-48119170-A-G is Benign according to our data. Variant chr19-48119170-A-G is described in ClinVar as [Benign]. Clinvar id is 403034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.84 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG1	NM_000234.3	c.2406T>C	p.Asp802=	synonymous_variant	25/28	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.2406T>C	p.Asp802=	synonymous_variant	25/28	1	NM_000234.3	ENSP00000263274	P4
	ENST00000596563.5	n.69+670A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97228 AN: 152010 Hom.: 32620 Cov.: 32

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.527

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.614

GnomAD3 exomes AF: 0.576 AC: 115798 AN: 201046 Hom.: 34721 AF XY: 0.570 AC XY: 61578 AN XY: 107956

Gnomad AFR exome AF: 0.853

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.484

Gnomad EAS exome AF: 0.878

Gnomad SAS exome AF: 0.554

Gnomad FIN exome AF: 0.574

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.558 AC: 797677 AN: 1429532 Hom.: 226941 Cov.: 43 AF XY: 0.557 AC XY: 394179 AN XY: 708144

Gnomad4 AFR exome AF: 0.861

Gnomad4 AMR exome AF: 0.515

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.866

Gnomad4 SAS exome AF: 0.548

Gnomad4 FIN exome AF: 0.571

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.584

GnomAD4 genome AF: 0.640 AC: 97333 AN: 152128 Hom.: 32670 Cov.: 32 AF XY: 0.637 AC XY: 47381 AN XY: 74366

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.542

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.868

Gnomad4 SAS AF: 0.555

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.544

Gnomad4 OTH AF: 0.615

Alfa AF: 0.556 Hom.: 27181

Bravo AF: 0.651

Asia WGS AF: 0.745 AC: 2590 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	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 74% of patients studied by a panel of primary immunodeficiencies. Number of patients: 71. Only high quality variants are reported. -
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 -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.076
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs20581; hg19: chr19-48622427; COSMIC: COSV54391114; COSMIC: COSV54391114;