chr19-48137550-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000234.3(LIG1):c.1226G>A(p.Arg409His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 1,613,334 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 17 hom., cov: 32)

Exomes 𝑓: 0.019 ( 301 hom. )

Consequence

LIG1
NM_000234.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.498

Publications

15 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032405555).

BP6

Variant 19-48137550-C-T is Benign according to our data. Variant chr19-48137550-C-T is described in ClinVar as [Benign]. Clinvar id is 1169833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1923/152336) while in subpopulation NFE AF = 0.0201 (1364/68024). AF 95% confidence interval is 0.0192. There are 17 homozygotes in GnomAd4. There are 927 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG1	NM_000234.3 link	c.1226G>A	p.Arg409His	missense_variant	Exon 13 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.1226G>A	p.Arg409His	missense_variant	Exon 13 of 28	1	NM_000234.3	ENSP00000263274.6		P18858-1

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1924

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.0800

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0200

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0131

AC:

3271

AN:

249096

AF XY:

0.0139

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00573

Gnomad ASJ exome

AF:

0.00676

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00600

Gnomad NFE exome

AF:

0.0205

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.0188

AC:

27537

AN:

1460998

Hom.:

301

Cov.:

AF XY:

0.0188

AC XY:

13687

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33478

American (AMR)

AF:

0.00566

AC:

253

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00693

AC:

181

AN:

26126

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0147

AC:

1271

AN:

86252

European-Finnish (FIN)

AF:

0.00736

AC:

387

AN:

52612

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0218

AC:

24221

AN:

1111968

Other (OTH)

AF:

0.0176

AC:

1064

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1709

3417

5126

6834

8543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

920

1840

2760

3680

4600

<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:

0.0126

AC:

1923

AN:

152336

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

927

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00368

AC:

153

AN:

41586

American (AMR)

AF:

0.00889

AC:

136

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00806

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0137

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0201

AC:

1364

AN:

68024

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

198

296

395

494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0179

Hom.:

123

Bravo

AF:

0.0123

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0202

AC:

174

ExAC

AF:

0.0137

AC:

1660

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.25

T;.;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.059

LIST_S2

Uncertain

0.95

D;D;D;D

MetaRNN

Benign

0.0032

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.;L

PhyloP100

0.50

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.0

D;D;D;.

REVEL

Benign

0.042

Sift

Benign

0.39

T;D;T;.

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

0.54

P;P;.;.

Vest4

0.14

MPC

0.68

ClinPred

0.027

GERP RS

-0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.27

Mutation Taster

=94/6

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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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