rs3093765

Positions:

chr13-108210578-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_206937.2(LIG4):c.691C>T(p.Pro231Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

LIG4
NM_206937.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 9.51

Variant links:

Genes affected

LIG4 (HGNC:6601): (DNA ligase 4) The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

LIG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32838106).

BP6

Variant 13-108210578-G-A is Benign according to our data. Variant chr13-108210578-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 834697.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG4	NM_206937.2 linkuse as main transcript	c.691C>T	p.Pro231Ser	missense_variant	3/3	ENST00000442234.6	NP_996820.1	P49917A0A024RE06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG4	ENST00000442234.6 linkuse as main transcript	c.691C>T	p.Pro231Ser	missense_variant	3/3	1	NM_206937.2	ENSP00000402030.1		P49917

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250152

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1460870

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726750

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000427

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000160

Hom.:

Bravo

AF:

0.000465

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 06, 2022

DNA sequence analysis of the LIG4 gene demonstrated a sequence change, c.691C>T, in exon 2 that results in an amino acid change, p.Pro231Ser. This sequence change does not appear to have been previously described in individuals with LIG4-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.1485% in the African/African American subpopulation (dbSNP rs3093765). The p.Pro231Ser change affects a highly conserved amino acid residue located in a domain of the LIG4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro231Ser substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro231Ser change remains unknown at this time. -

Multiple myeloma;C1847827:DNA ligase IV deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

DNA ligase IV deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;D;D;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;.;.;D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Uncertain

-0.081

MutationAssessor

Pathogenic

3.0

M;M;M;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.0

D;.;D;D;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.0060

D;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.78

P;P;P;P;.

Vest4

0.68

MVP

0.81

MPC

0.092

ClinPred

0.16

GERP RS

5.7

Varity_R

0.60

gMVP

0.55

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over