rs3730980

Variant names:

• chr19-48135765-T-C
• rs3730980
• NM_000234.3:c.1438A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000234.3(LIG1):​c.1438A>G​(p.Met480Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,838 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (16 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.32
• Publications: 8 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: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024951994).
• BP6: Variant 19-48135765-T-C is Benign according to our data. Variant chr19-48135765-T-C is described in ClinVar as Benign. ClinVar VariationId is 1164606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00825 (1257/152272) while in subpopulation AFR AF = 0.0287 (1192/41560). AF 95% confidence interval is 0.0273. There are 13 homozygotes in GnomAd4. There are 596 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	NM_000234.3	MANE Select	c.1438A>G	p.Met480Val	missense	Exon 16 of 28	NP_000225.1	P18858-1
	LIG1	NM_001320970.2		c.1435A>G	p.Met479Val	missense	Exon 16 of 28	NP_001307899.1	A0A8V8TQC4
	LIG1	NM_001320971.2		c.1348A>G	p.Met450Val	missense	Exon 15 of 27	NP_001307900.1	A0A8V8TPH8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIG1	ENST00000263274.12	TSL:1 MANE Select	c.1438A>G	p.Met480Val	missense	Exon 16 of 28	ENSP00000263274.6	P18858-1
	LIG1	ENST00000594759.5	TSL:1	n.1435A>G		non_coding_transcript_exon	Exon 16 of 28	ENSP00000471380.1	M0R0Q7
	LIG1	ENST00000916675.1		c.1540A>G	p.Met514Val	missense	Exon 16 of 28	ENSP00000586734.1

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1255 AN: 152154 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00210 AC: 528 AN: 251448 AF XY: 0.00152

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000771 AC: 1127 AN: 1461566 Hom.: 16 Cov.: 32 AF XY: 0.000619 AC XY: 450 AN XY: 727116

African (AFR) AF: 0.0272 AC: 912 AN: 33470

American (AMR) AF: 0.00174 AC: 78 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111750

Other (OTH) AF: 0.00186 AC: 112 AN: 60374

GnomAD4 genome AF: 0.00825 AC: 1257 AN: 152272 Hom.: 13 Cov.: 32 AF XY: 0.00800 AC XY: 596 AN XY: 74454

African (AFR) AF: 0.0287 AC: 1192 AN: 41560

American (AMR) AF: 0.00327 AC: 50 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00312 Hom.: 10

Bravo AF: 0.00978

ESP6500AA AF: 0.0291 AC: 128

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	LIG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.83
DANN	Benign	0.88
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		2.3
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.077
MVP		0.048
MPC		0.28
ClinPred		0.0022	T
GERP RS		3.9
Varity_R		0.34
gMVP		0.39
Mutation Taster		=96/4	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: rs3730980; hg19: chr19-48639022; COSMIC: COSV99074767; COSMIC: COSV99074767;