rs3730947

Positions:

• chr19-48140013-C-T

Variant summary

Our verdict is Benign. Variant got -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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 1164110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48140013-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIG1	NM_000234.3	c.1045G>A	p.Val349Met	missense_variant	12/28	ENST00000263274.12	NP_000225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIG1	ENST00000263274.12	c.1045G>A	p.Val349Met	missense_variant	12/28	1	NM_000234.3	ENSP00000263274	P4

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

GnomAD3 exomes AF: 0.00366 AC: 920 AN: 251376 Hom.: 6 AF XY: 0.00375 AC XY: 509 AN XY: 135886

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 SAS exome AF: 0.00559

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

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00945

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00551

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.00281

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

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.0165

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00233 Hom.: 1

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

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	LIG1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;.;M
MutationTaster	Benign	0.76	D;D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N;N;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs3730947; hg19: chr19-48643270; COSMIC: COSV54392177; COSMIC: COSV54392177;