NM_000234.3:c.2676G>T

Variant names:

• chr19-48115873-C-A
• rs11666150
• NM_000234.3:c.2676G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000234.3(LIG1):​c.2676G>T​(p.Gln892His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q892Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIG1 NM_000234.3 missense, splice_region
• Scores: Splicing: ADA: 0.9966
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38
• Publications: 4 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: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2676G>T	p.Gln892His	missense splice_region	Exon 27 of 28	NP_000225.1
	LIG1	NM_001320970.2		c.2673G>T	p.Gln891His	missense splice_region	Exon 27 of 28	NP_001307899.1
	LIG1	NM_001320971.2		c.2586G>T	p.Gln862His	missense splice_region	Exon 26 of 27	NP_001307900.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	ENST00000263274.12	TSL:1 MANE Select	c.2676G>T	p.Gln892His	missense splice_region	Exon 27 of 28	ENSP00000263274.6
	LIG1	ENST00000594759.5	TSL:1	n.*1273G>T		splice_region non_coding_transcript_exon	Exon 27 of 28	ENSP00000471380.1
	LIG1	ENST00000594759.5	TSL:1	n.*1273G>T		3_prime_UTR	Exon 27 of 28	ENSP00000471380.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000707 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.4
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.79	P
Vest4		0.54
MutPred		0.45		Gain of catalytic residue at Q892 (P = 0.0524)
MVP		0.71
MPC		0.79
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.68
gMVP		0.61
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.16		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: rs11666150; hg19: chr19-48619130;