19-48115899-G-A

Position:

• chr19-48115899-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000234.3(LIG1):​c.2650C>T​(p.Pro884Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG1	NM_000234.3	c.2650C>T	p.Pro884Ser	missense_variant	27/28	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.2650C>T	p.Pro884Ser	missense_variant	27/28	1	NM_000234.3	ENSP00000263274	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000532 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.2650C>T (p.P884S) alteration is located in exon 27 (coding exon 26) of the LIG1 gene. This alteration results from a C to T substitution at nucleotide position 2650, causing the proline (P) at amino acid position 884 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Benign	0.25
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.88	P;P;.
Vest4		0.52
MutPred		0.43		Loss of helix (P = 0.0237);.;.;
MVP		0.68
MPC		0.30
ClinPred		0.97	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.69
gMVP		0.63

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

Other links and lift over

dbSNP: rs2032771255; hg19: chr19-48619156;