Genetic Variant LIG1:p.Arg771Gly (chr19-48121244-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000234.3(LIG1):c.2311C>G(p.Arg771Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R771W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

LIG1
NM_000234.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.24

Publications

18 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

LIG1 links:

ENSG00000269534 (HGNC:):

ENSG00000269534 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-48121244-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16776.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000234.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIG1	NM_000234.3	MANE Select	c.2311C>G	p.Arg771Gly	missense	Exon 24 of 28	NP_000225.1	P18858-1
LIG1	NM_001320970.2		c.2308C>G	p.Arg770Gly	missense	Exon 24 of 28	NP_001307899.1	A0A8V8TQC4
LIG1	NM_001320971.2		c.2221C>G	p.Arg741Gly	missense	Exon 23 of 27	NP_001307900.1	A0A8V8TPH8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIG1	ENST00000263274.12	TSL:1 MANE Select	c.2311C>G	p.Arg771Gly	missense	Exon 24 of 28	ENSP00000263274.6	P18858-1
LIG1	ENST00000594759.5	TSL:1	n.2308C>G		non_coding_transcript_exon	Exon 24 of 28	ENSP00000471380.1	M0R0Q7
LIG1	ENST00000916675.1		c.2413C>G	p.Arg805Gly	missense	Exon 24 of 28	ENSP00000586734.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

0.80

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

3.7

PhyloP100

2.2

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.84

Loss of MoRF binding (P = 0.0283)

MVP

0.81

MPC

1.1

ClinPred

1.0

GERP RS

4.2

Varity_R

0.97

gMVP

0.90

Mutation Taster

=20/80

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over