Genetic Variant LIG1:p.Gln900Gln (chr19-48115709-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000234.3(LIG1):c.2700A>G(p.Gln900Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,614,128 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 36 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

LIG1
NM_000234.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.121

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 19-48115709-T-C is Benign according to our data. Variant chr19-48115709-T-C is described in ClinVar as [Benign]. Clinvar id is 1164975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.121 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0111 (1683/152298) while in subpopulation AFR AF = 0.0372 (1545/41566). AF 95% confidence interval is 0.0356. There are 36 homozygotes in GnomAd4. There are 805 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG1	NM_000234.3 link	c.2700A>G	p.Gln900Gln	synonymous_variant	Exon 28 of 28	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.2700A>G	p.Gln900Gln	synonymous_variant	Exon 28 of 28	1	NM_000234.3	ENSP00000263274.6		P18858-1

Frequencies

GnomAD3 genomes

AF:

0.0110

AC:

1677

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0371

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00290

AC:

730

AN:

251394

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.0385

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00109

AC:

1594

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000921

AC XY:

670

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0375

AC:

1254

AN:

33470

American (AMR)

AF:

0.00266

AC:

119

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1111964

Other (OTH)

AF:

0.00260

AC:

157

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

182

272

363

454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0111

AC:

1683

AN:

152298

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

805

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0372

AC:

1545

AN:

41566

American (AMR)

AF:

0.00725

AC:

111

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

181

271

362

452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00622

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

3.9

(source)

DANN

Benign

0.75

PhyloP100

0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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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19-48115709-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over