Genetic Variant LIG1:c.-58+330A>G (chr19-48169911-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000234.3(LIG1):c.-58+330A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 10)

Exomes 𝑓: 0.00043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LIG1
NM_000234.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.69

Publications

1 publications found

Variant links:

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]

LIG1 Gene-Disease associations (from GenCC):

immunodeficiency 96
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

LIG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (779/73034) while in subpopulation AFR AF = 0.0278 (425/15284). AF 95% confidence interval is 0.0256. There are 13 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 10. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG1	NM_000234.3 link	c.-58+330A>G		intron_variant	Intron 1 of 27	ENST00000263274.12	NP_000225.1	P18858-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12 link	c.-58+330A>G		intron_variant	Intron 1 of 27	1	NM_000234.3	ENSP00000263274.6		P18858-1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

774

AN:

72984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0276

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00855

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.00791

Gnomad SAS

AF:

0.00660

Gnomad FIN

AF:

0.00779

Gnomad MID

AF:

0.0286

Gnomad NFE

AF:

0.00440

Gnomad OTH

AF:

0.00696

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000431

AC:

AN:

6958

Hom.:

Cov.:

AF XY:

0.000716

AC XY:

AN XY:

4188

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

158

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.000791

AC:

AN:

2528

European-Finnish (FIN)

AF:

0.00

AC:

AN:

292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000274

AC:

AN:

3652

Other (OTH)

AF:

0.00

AC:

AN:

264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0107

AC:

779

AN:

73034

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

380

AN XY:

34490

show subpopulations

African (AFR)

AF:

0.0278

AC:

425

AN:

15284

American (AMR)

AF:

0.00854

AC:

AN:

7732

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

2180

East Asian (EAS)

AF:

0.00794

AC:

AN:

2014

South Asian (SAS)

AF:

0.00664

AC:

AN:

1958

European-Finnish (FIN)

AF:

0.00779

AC:

AN:

3852

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.00440

AC:

169

AN:

38406

Other (OTH)

AF:

0.00688

AC:

AN:

1018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.7

(source)

DANN

Benign

0.39

PhyloP100

-2.7

PromoterAI

0.020

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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19-48169911-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over