chr19-48135765-T-C

Position:

• chr19-48135765-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000263274.12(LIG1):​c.1438A>G​(p.Met480Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,838 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0083 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (16 hom.)
• Consequence: LIG1 ENST00000263274.12 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.32

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 (MetaRNN=0.0024951994).
• BP6: Variant 19-48135765-T-C is Benign according to our data. Variant chr19-48135765-T-C is described in ClinVar as [Benign]. Clinvar id is 1164606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00825 (1257/152272) while in subpopulation AFR AF= 0.0287 (1192/41560). AF 95% confidence interval is 0.0273. There are 13 homozygotes in gnomad4. There are 596 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG1	NM_000234.3	c.1438A>G	p.Met480Val	missense_variant	16/28	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.1438A>G	p.Met480Val	missense_variant	16/28	1	NM_000234.3	ENSP00000263274	P4

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1255 AN: 152154 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00210 AC: 528 AN: 251448 Hom.: 4 AF XY: 0.00152 AC XY: 206 AN XY: 135892

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000771 AC: 1127 AN: 1461566 Hom.: 16 Cov.: 32 AF XY: 0.000619 AC XY: 450 AN XY: 727116

Gnomad4 AFR exome AF: 0.0272

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00825 AC: 1257 AN: 152272 Hom.: 13 Cov.: 32 AF XY: 0.00800 AC XY: 596 AN XY: 74454

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00195 Hom.: 4

Bravo AF: 0.00978

ESP6500AA AF: 0.0291 AC: 128

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

LIG1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.83
DANN	Benign	0.88
DEOGEN2	Benign	0.092	T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.34	T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N;.;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	1.6	N;N;N;.
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.077
MVP		0.048
MPC		0.28
ClinPred		0.0022	T
GERP RS		3.9
Varity_R		0.34
gMVP		0.39

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: rs3730980; hg19: chr19-48639022; COSMIC: COSV99074767; COSMIC: COSV99074767;