19-48143984-T-C

Variant names:

• chr19-48143984-T-C
• rs3730931
• NM_000234.3:c.777-21A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000234.3(LIG1):​c.777-21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,579,302 control chromosomes in the GnomAD database, including 12,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2023 hom., cov: 31)
  • Exomes 𝑓: 0.12 (10302 hom.)
• Consequence: LIG1 NM_000234.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.25
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-48143984-T-C is Benign according to our data. Variant chr19-48143984-T-C is described in ClinVar as Benign. ClinVar VariationId is 2628268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

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.777-21A>G		intron	N/A	NP_000225.1	P18858-1
	LIG1	NM_001320970.2		c.774-21A>G		intron	N/A	NP_001307899.1	A0A8V8TQC4
	LIG1	NM_001320971.2		c.687-21A>G		intron	N/A	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.777-21A>G		intron	N/A	ENSP00000263274.6	P18858-1
	LIG1	ENST00000594759.5	TSL:1	n.774-21A>G		intron	N/A	ENSP00000471380.1	M0R0Q7
	LIG1	ENST00000916675.1		c.777-21A>G		intron	N/A	ENSP00000586734.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22965 AN: 151866 Hom.: 2022 Cov.: 31

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0899

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.0862

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.119 AC: 29971 AN: 251408 AF XY: 0.114

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.127

Gnomad FIN exome AF: 0.0887

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.117 AC: 166592 AN: 1427318 Hom.: 10302 Cov.: 28 AF XY: 0.115 AC XY: 81885 AN XY: 712344

African (AFR) AF: 0.264 AC: 8637 AN: 32680

American (AMR) AF: 0.133 AC: 5962 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0855 AC: 2218 AN: 25928

East Asian (EAS) AF: 0.0991 AC: 3913 AN: 39490

South Asian (SAS) AF: 0.0824 AC: 7050 AN: 85530

European-Finnish (FIN) AF: 0.0908 AC: 4848 AN: 53402

Middle Eastern (MID) AF: 0.0790 AC: 452 AN: 5718

European-Non Finnish (NFE) AF: 0.117 AC: 126417 AN: 1080718

Other (OTH) AF: 0.120 AC: 7095 AN: 59168

GnomAD4 genome AF: 0.151 AC: 22984 AN: 151984 Hom.: 2023 Cov.: 31 AF XY: 0.148 AC XY: 10979 AN XY: 74290

African (AFR) AF: 0.255 AC: 10565 AN: 41414

American (AMR) AF: 0.131 AC: 1999 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0899 AC: 312 AN: 3472

East Asian (EAS) AF: 0.120 AC: 621 AN: 5172

South Asian (SAS) AF: 0.0812 AC: 391 AN: 4818

European-Finnish (FIN) AF: 0.0862 AC: 912 AN: 10582

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.115 AC: 7831 AN: 67952

Other (OTH) AF: 0.127 AC: 268 AN: 2110

Alfa AF: 0.139 Hom.: 579

Bravo AF: 0.160

Asia WGS AF: 0.120 AC: 419 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.34
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3730931; hg19: chr19-48647241; COSMIC: COSV54391159; COSMIC: COSV54391159;