19-48161460-G-C

Variant names:

• chr19-48161460-G-C
• rs4987181
• NM_000234.3:c.155C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000234.3(LIG1):​c.155C>G​(p.Pro52Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. P52L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36913294).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	NM_000234.3	MANE Select	c.155C>G	p.Pro52Arg	missense	Exon 4 of 28	NP_000225.1	P18858-1
	LIG1	NM_001320970.2		c.155C>G	p.Pro52Arg	missense	Exon 4 of 28	NP_001307899.1	A0A8V8TQC4
	LIG1	NM_001320971.2		c.65C>G	p.Pro22Arg	missense	Exon 3 of 27	NP_001307900.1	A0A8V8TPH8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	ENST00000263274.12	TSL:1 MANE Select	c.155C>G	p.Pro52Arg	missense	Exon 4 of 28	ENSP00000263274.6	P18858-1
	LIG1	ENST00000594759.5	TSL:1	n.155C>G		non_coding_transcript_exon	Exon 4 of 28	ENSP00000471380.1	M0R0Q7
	LIG1	ENST00000916675.1		c.155C>G	p.Pro52Arg	missense	Exon 4 of 28	ENSP00000586734.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.090	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.25		Gain of MoRF binding (P = 0.0423)
MVP		0.76
MPC		0.99
ClinPred		0.96	D
GERP RS		4.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.38
gMVP		0.52
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4987181; hg19: chr19-48664717;