Genetic Variant NM_000234.3:c.1821+35G>A (chr19-48131041-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000234.3(LIG1):c.1821+35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,562,268 control chromosomes in the GnomAD database, including 12,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.15 ( 2059 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10170 hom. )

Consequence

LIG1
NM_000234.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.628

Publications

4 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 19-48131041-C-T is Benign according to our data. Variant chr19-48131041-C-T is described in ClinVar as Benign. ClinVar VariationId is 2628267.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG1	NM_000234.3 link	c.1821+35G>A		intron_variant	Intron 19 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.1821+35G>A		intron_variant	Intron 19 of 27	1	NM_000234.3	ENSP00000263274.6		P18858-1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

23019

AN:

152166

Hom.:

2052

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.133

Gnomad ASJ

AF:

0.0899

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.0806

Gnomad FIN

AF:

0.0867

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.119

AC:

29824

AN:

250316

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.264

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.0836

Gnomad EAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.0887

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.117

AC:

164332

AN:

1409984

Hom.:

10170

Cov.:

AF XY:

0.115

AC XY:

80817

AN XY:

704408

show subpopulations

African (AFR)

AF:

0.263

AC:

8548

AN:

32468

American (AMR)

AF:

0.135

AC:

6012

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0857

AC:

2211

AN:

25790

East Asian (EAS)

AF:

0.0979

AC:

3861

AN:

39448

South Asian (SAS)

AF:

0.0819

AC:

6981

AN:

85280

European-Finnish (FIN)

AF:

0.0909

AC:

4831

AN:

53170

Middle Eastern (MID)

AF:

0.0784

AC:

443

AN:

5650

European-Non Finnish (NFE)

AF:

0.117

AC:

124415

AN:

1064896

Other (OTH)

AF:

0.120

AC:

7030

AN:

58650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

7806

15613

23419

31226

39032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4556

9112

13668

18224

22780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.151

AC:

23051

AN:

152284

Hom.:

2059

Cov.:

AF XY:

0.148

AC XY:

11053

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.255

AC:

10588

AN:

41540

American (AMR)

AF:

0.133

AC:

2034

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0899

AC:

312

AN:

3472

East Asian (EAS)

AF:

0.119

AC:

618

AN:

5178

South Asian (SAS)

AF:

0.0803

AC:

388

AN:

4832

European-Finnish (FIN)

AF:

0.0867

AC:

920

AN:

10616

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.115

AC:

7840

AN:

68022

Other (OTH)

AF:

0.126

AC:

266

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1006

2012

3017

4023

5029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.107

Hom.:

581

Bravo

AF:

0.160

Asia WGS

AF:

0.122

AC:

424

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.1

(source)

DANN

Benign

0.64

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism (auto)

(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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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