rs3731008

Variant names:

• chr19-48123293-C-A
• rs3731008
• NM_000234.3:c.2030G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-48123293-C-A
• chr19-48123293-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000234.3(LIG1):​c.2030G>T​(p.Arg677Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,613,744 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R677W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (8 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.403
• Publications: 7 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

ENSG00000269534 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013813436).
• BP6: Variant 19-48123293-C-A is Benign according to our data. Variant chr19-48123293-C-A is described in ClinVar as Benign. ClinVar VariationId is 788029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 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.2030G>T	p.Arg677Leu	missense	Exon 22 of 28	NP_000225.1	P18858-1
	LIG1	NM_001320970.2		c.2027G>T	p.Arg676Leu	missense	Exon 22 of 28	NP_001307899.1	A0A8V8TQC4
	LIG1	NM_001320971.2		c.1940G>T	p.Arg647Leu	missense	Exon 21 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.2030G>T	p.Arg677Leu	missense	Exon 22 of 28	ENSP00000263274.6	P18858-1
	LIG1	ENST00000594759.5	TSL:1	n.2027G>T		non_coding_transcript_exon	Exon 22 of 28	ENSP00000471380.1	M0R0Q7
	LIG1	ENST00000916675.1		c.2132G>T	p.Arg711Leu	missense	Exon 22 of 28	ENSP00000586734.1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152058 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00120 AC: 300 AN: 250862 AF XY: 0.000818

Gnomad AFR exome AF: 0.0162

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000432 AC: 632 AN: 1461568 Hom.: 5 Cov.: 32 AF XY: 0.000374 AC XY: 272 AN XY: 727098

African (AFR) AF: 0.0151 AC: 504 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111964

Other (OTH) AF: 0.000994 AC: 60 AN: 60390

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152176 Hom.: 8 Cov.: 31 AF XY: 0.00367 AC XY: 273 AN XY: 74396

African (AFR) AF: 0.0136 AC: 563 AN: 41518

American (AMR) AF: 0.00144 AC: 22 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00242 Hom.: 6

Bravo AF: 0.00454

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00159 AC: 193

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	LIG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.42	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.40
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.29
Sift	Uncertain	0.025	D
Sift4G	Benign	0.11	T
Polyphen		0.067	B
Vest4		0.56
MVP		0.50
MPC		0.37
ClinPred		0.021	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.40
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3731008; hg19: chr19-48626550; COSMIC: COSV105033937;