NM_000234.3:c.244-114T>C

Variant names:

• chr19-48157254-A-G
• rs3730865
• NM_000234.3:c.244-114T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000234.3(LIG1):​c.244-114T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,233,244 control chromosomes in the GnomAD database, including 1,036 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 0.026 (76 hom., cov: 31)
  • Exomes 𝑓: 0.039 (960 hom.)
• Consequence: LIG1 NM_000234.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.283
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0255 (3886/152184) while in subpopulation NFE AF = 0.0416 (2827/68002). AF 95% confidence interval is 0.0403. There are 76 homozygotes in GnomAd4. There are 1779 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 AR gene

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.244-114T>C		intron	N/A	NP_000225.1
	LIG1	NM_001320970.2		c.244-114T>C		intron	N/A	NP_001307899.1
	LIG1	NM_001320971.2		c.154-114T>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.244-114T>C		intron	N/A	ENSP00000263274.6
	LIG1	ENST00000594759.5	TSL:1	n.244-114T>C		intron	N/A	ENSP00000471380.1
	LIG1	ENST00000699868.1		c.244-114T>C		intron	N/A	ENSP00000514664.1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3889 AN: 152066 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.00529

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.0392 AC: 42371 AN: 1081060 Hom.: 960 AF XY: 0.0388 AC XY: 20782 AN XY: 535190

African (AFR) AF: 0.00598 AC: 150 AN: 25068

American (AMR) AF: 0.0209 AC: 554 AN: 26524

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 296 AN: 16146

East Asian (EAS) AF: 0.00 AC: 0 AN: 33138

South Asian (SAS) AF: 0.0225 AC: 1264 AN: 56266

European-Finnish (FIN) AF: 0.00669 AC: 281 AN: 42026

Middle Eastern (MID) AF: 0.0430 AC: 130 AN: 3026

European-Non Finnish (NFE) AF: 0.0457 AC: 38147 AN: 834314

Other (OTH) AF: 0.0348 AC: 1549 AN: 44552

GnomAD4 genome AF: 0.0255 AC: 3886 AN: 152184 Hom.: 76 Cov.: 31 AF XY: 0.0239 AC XY: 1779 AN XY: 74396

African (AFR) AF: 0.00802 AC: 333 AN: 41538

American (AMR) AF: 0.0262 AC: 400 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.0212 AC: 102 AN: 4818

European-Finnish (FIN) AF: 0.00529 AC: 56 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2827 AN: 68002

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0292 Hom.: 10

Bravo AF: 0.0270

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.97
DANN	Benign	0.79
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

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: rs3730865; hg19: chr19-48660511;