Variant chr13-108209993-CTCTTT-C details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-108209993-CTCTTT-C is Pathogenic according to our data. Variant chr13-108209993-CTCTTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 279838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-108209993-CTCTTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIG4	NM_206937.2 link	c.1271_1275delAAAGA	p.Lys424ArgfsTer20	frameshift_variant	Exon 3 of 3	ENST00000442234.6	NP_996820.1	P49917A0A024RE06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6 link	c.1271_1275delAAAGA	p.Lys424ArgfsTer20	frameshift_variant	Exon 3 of 3	1	NM_206937.2	ENSP00000402030.1		P49917

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

38

AN:

152220

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000156

AC:

39

AN:

250062

Hom.:

0

AF XY:

0.000155

AC XY:

21

AN XY:

135328

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000216

AC:

316

AN:

1460186

Hom.:

0

AF XY:

0.000202

AC XY:

147

AN XY:

726476

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000233

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000249

AC:

38

AN:

152338

Hom.:

0

Cov.:

32

AF XY:

0.000215

AC XY:

16

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000217

Hom.:

0

Bravo

AF:

0.000257

Asia WGS

AF:

0.000289

AC:

1

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DNA ligase IV deficiency

Pathogenic:6

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys424Argfs*20) in the LIG4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 488 amino acid(s) of the LIG4 protein. This variant is present in population databases (rs772226399, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of LIG4 syndrome (PMID: 16358631, 24123394, 27612988, 27893162, 29146883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as K424fs. ClinVar contains an entry for this variant (Variation ID: 279838). For these reasons, this variant has been classified as Pathogenic. -

-

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 moderate, PM3 very strong, PP1 moderate -

Jul 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LIG4 c.1271_1275delAAAGA (p.Lys424ArgfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 250062 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LIG4 causing LIG4 Syndrome, allowing no conclusion about variant significance. c.1271_1275delAAAGA has been reported in the literature as a biallelic genotype in multiple individuals affected with LIG4 Syndrome (example, Buck_2006, Murray_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete ablation of V(D)J recombination activity in-vitro (example, Buck_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16358361, 24123394). ClinVar contains an entry for this variant (Variation ID: 279838). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 18, 2018

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of LIG4 syndrome (most commonly immunodeficiency and failure to thrive), segregating with disease in at least 3 affected family members (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162, Jiang 2016 PMID:26762768, Walne 2016 PMID:27612988). This variant is present in 27/126568 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772226399). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:279838). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, functional studies suggest that this variant may result in increased sensitivity to radiation (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162). This variant represents a deletion of 5 nucelotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PM3_VeryStrong+PP1_Strong -

LIG4-related disorder

Pathogenic:3

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LIG4 c.1271_1275delAAAGA (p.Lys424ArgfsTer20) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Lys424ArgfsTer20 variant has been reported in five studies in which it is found in a compound heterozygous state in 14 individuals with LIG4-related disorders from 11 unrelated families (Buck et al. 2006; Enders et al. 2006; Murray et al. 2014; Jiang et al. 2016; Walne et al. 2016). In all cases, the p.Lys424ArgfsTer20 variant was inherited from a healthy heterozygous parent. Two of these patients were diagnosed with dyskeratosis congenita; the authors state that clinical symptoms in these patients had substantial overlap with LIG4 syndrome (Walne et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. Buck et al. (2006) showed that Lig4 protein expression in fibroblasts from one patient was significantly reduced compared to wild type, and a cell survival assay in fibroblasts from a second patient showed increased sensitivity to ionizing radiation. Based on the evidence and potential impact of frameshift variants, the p.Lys424ArgfsTer20 is classified as pathogenic for LIG4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LIG4 c.1271_1275del5 variant is predicted to result in a frameshift and premature protein termination (p.Lys424Argfs*20). This variant has been reported in the compound heterozygous state in multiple individuals with clinical features of LIG4 syndrome and segregates with disease in several families (Buck et al. 2006. PubMed ID: 16358361; Walne et al. 2016. PubMed ID: 27612988; Cifaldi et al. 2017. PubMed ID: 27893162; Staines Boone et al. 2018. PubMed ID: 30719430; Bluteau et al. 2018. PubMed ID: 29146883; Duerinckx et al. 2020. PubMed ID: 31696992). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Frameshift variants in LIG4 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:2

Oct 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on Lig4 protein levels (Buck et al., 2006); Frameshift variant predicted to result in protein truncation, as the last 488 amino acids are replaced with 19 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 27893162, 26762768, 16358361, 27612988, 16585603, 24123394, 30719430, 31696992, 31980526, 34426522, 29146883, 32471509, 31589614, 35595529, 34313030, 34630384, 35665479, 37437665, 36221079) -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LIG4: PVS1, PM3, PM2:Supporting -

Multiple myeloma;C1847827:DNA ligase IV deficiency

Pathogenic:2

Apr 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LIG4 NM_002312.3 exon 2 p.Lys424Argfs*20 (c.1271_1275del): This variant has been reported as compound heterozygous in the literature in at least 11 individuals with features of LIG4 syndrome (most commonly immunodeficiency and failure to thrive), segregating with disease in at least 3 affected family members (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162, Jiang 2016 PMID:26762768, Walne 2016 PMID:27612988). This variant is present in 27/126568 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs772226399). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:279838). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, functional studies suggest that this variant may result in increased sensitivity to radiation (Buck 2006 PMID:16358361, Enders 2006 PMID:16585603, Murray 2014 PMID:24123394, Cifaldi 2016 PMID:27893162). This variant represents a deletion of 5 nucelotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene. In summary, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr13-108209993-CTCTTT-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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