19-48118562-A-G

Variant names:

• chr19-48118562-A-G
• rs3731043
• NM_000234.3:c.2439+575T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000234.3(LIG1):​c.2439+575T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0608 in 109,442 control chromosomes in the GnomAD database, including 246 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.061 (246 hom., cov: 21)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIG1 NM_000234.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.571
• Publications: 2 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)

ENSG00000269534 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0824 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	NM_000234.3	MANE Select	c.2439+575T>C		intron	N/A	NP_000225.1
	LIG1	NM_001320970.2		c.2436+575T>C		intron	N/A	NP_001307899.1
	LIG1	NM_001320971.2		c.2349+575T>C		intron	N/A	NP_001307900.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	ENST00000263274.12	TSL:1 MANE Select	c.2439+575T>C		intron	N/A	ENSP00000263274.6
	LIG1	ENST00000594759.5	TSL:1	n.*1036+575T>C		intron	N/A	ENSP00000471380.1
	LIG1	ENST00000699868.1		c.2439+575T>C		intron	N/A	ENSP00000514664.1

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 6653 AN: 109418 Hom.: 246 Cov.: 21

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0111

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.0566

Gnomad EAS AF: 0.000700

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0842

Gnomad NFE AF: 0.0845

Gnomad OTH AF: 0.0485

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 156

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 26

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 232

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.0608 AC: 6651 AN: 109442 Hom.: 246 Cov.: 21 AF XY: 0.0603 AC XY: 3092 AN XY: 51238

African (AFR) AF: 0.0152 AC: 428 AN: 28098

American (AMR) AF: 0.0472 AC: 447 AN: 9474

Ashkenazi Jewish (ASJ) AF: 0.0566 AC: 172 AN: 3038

East Asian (EAS) AF: 0.000701 AC: 2 AN: 2854

South Asian (SAS) AF: 0.0209 AC: 69 AN: 3296

European-Finnish (FIN) AF: 0.158 AC: 741 AN: 4700

Middle Eastern (MID) AF: 0.0795 AC: 14 AN: 176

European-Non Finnish (NFE) AF: 0.0844 AC: 4702 AN: 55678

Other (OTH) AF: 0.0482 AC: 68 AN: 1410

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.0
DANN	Benign	0.69
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3731043; hg19: chr19-48621819;