rs3730947

Variant names:

• chr19-48140013-C-T
• rs3730947
• NM_000234.3:c.1045G>A

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.1045G>A​(p.Val349Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,156 control chromosomes in the GnomAD database, including 19 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (18 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.416
• Publications: 14 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014671981).
• BP6: Variant 19-48140013-C-T is Benign according to our data. Variant chr19-48140013-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1164110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.1045G>A	p.Val349Met	missense	Exon 12 of 28	NP_000225.1	P18858-1
	LIG1	NM_001320970.2		c.1042G>A	p.Val348Met	missense	Exon 12 of 28	NP_001307899.1	A0A8V8TQC4
	LIG1	NM_001320971.2		c.955G>A	p.Val319Met	missense	Exon 11 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.1045G>A	p.Val349Met	missense	Exon 12 of 28	ENSP00000263274.6	P18858-1
	LIG1	ENST00000594759.5	TSL:1	n.1042G>A		non_coding_transcript_exon	Exon 12 of 28	ENSP00000471380.1	M0R0Q7
	LIG1	ENST00000916675.1		c.1045G>A	p.Val349Met	missense	Exon 12 of 28	ENSP00000586734.1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00537

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00366 AC: 920 AN: 251376 AF XY: 0.00375

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00268 AC: 3921 AN: 1461810 Hom.: 18 Cov.: 32 AF XY: 0.00280 AC XY: 2039 AN XY: 727206

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00945 AC: 247 AN: 26136

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

South Asian (SAS) AF: 0.00551 AC: 475 AN: 86258

European-Finnish (FIN) AF: 0.0153 AC: 814 AN: 53342

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00196 AC: 2178 AN: 1112006

Other (OTH) AF: 0.00281 AC: 170 AN: 60396

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74494

African (AFR) AF: 0.000577 AC: 24 AN: 41582

American (AMR) AF: 0.000523 AC: 8 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4834

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00220 Hom.: 4

Bravo AF: 0.00145

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00329 AC: 399

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.089	N
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.42
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.44
MPC		0.81
ClinPred		0.035	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.56
Mutation Taster		=93/7	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: rs3730947; hg19: chr19-48643270; COSMIC: COSV54392177; COSMIC: COSV54392177;