NM_000234.3:c.2442G>C

Variant names:

• chr19-48117779-C-G
• rs13436
• NM_000234.3:c.2442G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000234.3(LIG1):​c.2442G>C​(p.Ala814Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,611,088 control chromosomes in the GnomAD database, including 162,858 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A814A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17579 hom., cov: 34)
  • Exomes 𝑓: 0.44 (145279 hom.)
• Consequence: LIG1 NM_000234.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.688
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-48117779-C-G is Benign according to our data. Variant chr19-48117779-C-G is described in ClinVar as Benign. ClinVar VariationId is 403033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.688 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.73 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.2442G>C	p.Ala814Ala	splice_region synonymous	Exon 26 of 28	NP_000225.1
	LIG1	NM_001320970.2		c.2439G>C	p.Ala813Ala	splice_region synonymous	Exon 26 of 28	NP_001307899.1
	LIG1	NM_001320971.2		c.2352G>C	p.Ala784Ala	splice_region synonymous	Exon 25 of 27	NP_001307900.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	ENST00000263274.12	TSL:1 MANE Select	c.2442G>C	p.Ala814Ala	splice_region synonymous	Exon 26 of 28	ENSP00000263274.6
	LIG1	ENST00000594759.5	TSL:1	n.*1039G>C		splice_region non_coding_transcript_exon	Exon 26 of 28	ENSP00000471380.1
	LIG1	ENST00000594759.5	TSL:1	n.*1039G>C		3_prime_UTR	Exon 26 of 28	ENSP00000471380.1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72135 AN: 152012 Hom.: 17560 Cov.: 34

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.750

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.463 AC: 113343 AN: 244628 AF XY: 0.464

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.754

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.453

GnomAD4 exome AF: 0.441 AC: 643367 AN: 1458958 Hom.: 145279 Cov.: 46 AF XY: 0.442 AC XY: 320384 AN XY: 725416

African (AFR) AF: 0.547 AC: 18295 AN: 33458

American (AMR) AF: 0.381 AC: 16865 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10351 AN: 25994

East Asian (EAS) AF: 0.769 AC: 30484 AN: 39634

South Asian (SAS) AF: 0.468 AC: 40030 AN: 85560

European-Finnish (FIN) AF: 0.483 AC: 25648 AN: 53140

Middle Eastern (MID) AF: 0.464 AC: 2678 AN: 5766

European-Non Finnish (NFE) AF: 0.424 AC: 471218 AN: 1110802

Other (OTH) AF: 0.461 AC: 27798 AN: 60294

GnomAD4 genome AF: 0.475 AC: 72196 AN: 152130 Hom.: 17579 Cov.: 34 AF XY: 0.475 AC XY: 35353 AN XY: 74384

African (AFR) AF: 0.544 AC: 22573 AN: 41496

American (AMR) AF: 0.402 AC: 6140 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3470

East Asian (EAS) AF: 0.750 AC: 3879 AN: 5174

South Asian (SAS) AF: 0.474 AC: 2285 AN: 4822

European-Finnish (FIN) AF: 0.497 AC: 5273 AN: 10602

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29105 AN: 67974

Other (OTH) AF: 0.481 AC: 1015 AN: 2112

Alfa AF: 0.400 Hom.: 3715

Bravo AF: 0.474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.5
DANN	Benign	0.78
PhyloP100		0.69
Mutation Taster		=94/6	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: rs13436; hg19: chr19-48621036; COSMIC: COSV54392236; COSMIC: COSV54392236;