rs4987069

Positions:

• chr19-48137645-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000234.3(LIG1):​c.1131C>T​(p.Gly377=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,608,854 control chromosomes in the GnomAD database, including 239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (9 hom., cov: 32)
  • Exomes 𝑓: 0.015 (230 hom.)
• Consequence: LIG1 NM_000234.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.40

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=-0.85).
• BP6: Variant 19-48137645-G-A is Benign according to our data. Variant chr19-48137645-G-A is described in ClinVar as [Benign]. Clinvar id is 403036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0147 (21419/1456518) while in subpopulation NFE AF= 0.017 (18932/1111566). AF 95% confidence interval is 0.0168. There are 230 homozygotes in gnomad4_exome. There are 10313 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG1	NM_000234.3	c.1131C>T	p.Gly377=	synonymous_variant	13/28	ENST00000263274.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG1	ENST00000263274.12	c.1131C>T	p.Gly377=	synonymous_variant	13/28	1	NM_000234.3	P4

Frequencies

GnomAD3 genomes AF: 0.00918 AC: 1397 AN: 152218 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00912 AC: 2220 AN: 243422 Hom.: 18 AF XY: 0.00891 AC XY: 1182 AN XY: 132714

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00921

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0147 AC: 21419 AN: 1456518 Hom.: 230 Cov.: 32 AF XY: 0.0142 AC XY: 10313 AN XY: 724798

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00316

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00230

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.00917 AC: 1397 AN: 152336 Hom.: 9 Cov.: 32 AF XY: 0.00854 AC XY: 636 AN XY: 74478

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.0122 Hom.: 5

Bravo AF: 0.00819

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0126

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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	LIG1: BP4, BP7, BS1, BS2 -

not specified Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.29
DANN	Benign	0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs4987069; hg19: chr19-48640902; COSMIC: COSV99619623; COSMIC: COSV99619623;