rs41555118

chr19-48161475-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000234.3(LIG1):c.140C>T(p.Ser47Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0009 in 1,614,126 control chromosomes in the GnomAD database, including 8 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S47S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00088 (7 hom.)
• Consequence: LIG1 NM_000234.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.14

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046947896).
• BP6: Variant 19-48161475-G-A is Benign according to our data. Variant chr19-48161475-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 734140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48161475-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIG1	NM_000234.3	c.140C>T	p.Ser47Phe	missense_variant	4/28	ENST00000263274.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIG1	ENST00000263274.12	c.140C>T	p.Ser47Phe	missense_variant	4/28	1	NM_000234.3	P4

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152138 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00125 AC: 315 AN: 251320 Hom.: 1 AF XY: 0.00120 AC XY: 163 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000854

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.000881 AC: 1288 AN: 1461870 Hom.: 7 Cov.: 30 AF XY: 0.000901 AC XY: 655 AN XY: 727244

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152256 Hom.: 1 Cov.: 31 AF XY: 0.00105 AC XY: 78 AN XY: 74446

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Immunodeficiency 96 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0047	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N;N;N;.;.;.
REVEL	Benign	0.034
Sift	Uncertain	0.0040	D;D;D;.;.;.
Sift4G	Uncertain	0.050	T;D;D;T;.;.
Polyphen		0.20	B;P;.;.;.;.
Vest4		0.29
MVP		0.66
MPC		0.37
ClinPred		0.026	T
GERP RS		4.5
Varity_R		0.077
gMVP		0.099

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: rs41555118; hg19: chr19-48664732;